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University of Southern California Dissertations and Theses
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Studies on cactus alkaloids and related synthesic [i.e. Synthetic] compounds
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Studies on cactus alkaloids and related synthesic [i.e. Synthetic] compounds
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STUDIES ON CACTUS ALKALOIDS AND RELATED SiNTHESIC COt"iPOUriDS A • · e he · ult o the e niv s C 0 In i .T t d to e il y f ne t y p . ' 1 9 q This dissertation, written by I O I under the guidance of/;. ________ Faculty Committee on Studi s rind appro1 ed by all its members, has b n presented to and acr pted b, y th Coun ii 011 Gn,duat Study a11d R s arrh, in partial f,,l fil/111 , t of ,-equir 111 nt f r ti, d gre of DOCTOR OF PFIILOSOPHY ommitt 011 tudi Chairman ........ ................... .... ........ Dean AC GM T e wr t grat ully wishes to ac ow edge the c n iderate c un el and hel of Professors C.H. Thienes and k. J. agen-Srnit; the kin assistance of r. George eige in cert in o t oft e experimen al work, and th inva u e assi t· ce of r. Paul aun ers in the c rr cti an pr parati n oft 1 manu cript. CHAPTER I NTRODUC'I'IO.N l'ABLE OF CON'f l:11'f TS • • • • • • • • • • • • • • • • • • • CrlEMICAL S CTi r .N A. -ATUR ALLY OCCu I~U COMt Or S I . PR LIM NARY UHVEY • • • • • • • • • • • • II. EX'l 1 HAC1'ION .it AN ALKALOIDAL · B 'TANCE FROM T ICttOC~HEUS PACHI.AiiU Al~ ITS PAGE 1 9 ID ·~1IFI 'A'l!Oii A CAI l ICir ~ •••••••• 12 I II. PRr.:PAttATI l , O.tt ·u 11 rAI~ E ' o~· l'HE 3,4,5-T I:-i CJXYPH~NYL GR UP • • • • • • • 17 IV. p PARA 'I r .r· f>H 1 'l iL ~ .ALO u . . ITtl 8UH ~'IITUTI •rHER 3,4,5- T I!1 'T .. oxt • • • • • • • • • • • • • • • • 34 PHARMA U G ICA SECT! S v. COL GY • • • • • • • • • 36 VI. · P'ECT 0-291 HLOOlJ .H ' · ~utt · OF • • • • • • • • • 37 VII. TH~ E ·c 0-291 01 E T' I OLA " · Ir • • • • • • • • • 41,, VIII . !CITY F 0-291 I- MI E ••• • • • • • • 46 IX. ·FFECT r' 0-291 ON T.- RIV I 'OL T . A'f ' V ~'l' i C (,f; T IP • • • • • • • • • • • 49 x. I ·cu IN. • • • • • • • • • • • • • • • • 50 BIBLIOGRA~hY ••• • • • • • • • • • • • • • • • • 64 I TRODUCTION Primitive people all over the world have made use of plants for their medicinal or eu horic effect . Hundreds of years ela sed in cert in instances befor this mowledge fell un er t he crutiny of estern scienti t. Th s owness w·t w i ht ese lant _rinciple r adopte by th O c i- t peo it r em • _le , e 1 us coca h A r i t 0 r o Wi In h r ranee 1 • a h SC e i o- i e 1 d al dre an ur own t era r t b en o ar .e la f o s n Y P 0 t ad t ye r • e • r dia "· n o a - v for t cam f rr d t h to the r. Car cl s wn a ore it ma e r qu e ro • • C r na , s r In tte n r y C i o root" i n i hora r for f th not a 0 • 2 It was only in 1888 that the first serious attempt at chemical pharmacological study of this small Mexican cactus was made by Lewin. (1) In 1894 Heffter (2) became interested in this same problem, followed by Kauder (3) in 1899. Al though these authors succeeded in isolating c rtain of the active substances of the cactus, it was not until twenty •• years later that Spath (4) in a brilliant series of publica- ti ns spanning the years between 1919 t 1939, succeede in i entifying and synthe izing the el v n lk loi s tha r known tod y to exist in Lophophora willi Thi thor si ult eou ly i entified and synthesized s e 1 ids oun in other cacti. h lka - trangely enough, before L wi ' s ork , it w s 1 v h V t ca ti id n t cot in alkaloi ve ta C e of the a t a rea wave o in ere • On wo 1 n i e i t e C ave ·nitl t d a syst the o t pr ni in am n , the mor ic ana y han 1, cribed in the cactu f mily, ut t d t on_y i lly iv st ated. 0 o ld 0 t n een y te On o t r on for th a aren lack o i er in uc a rich fi el r es arch is 1 dubita ly t iffic lt es w ich are et in tain e ria. s, t i lly r C lant, 1 foun in re t i es on the sl es o the e , on es t at aus h an d in 3 the tropical forests of this continent. Some chemically un- interesting species are found elsewhere in the world. A contributing factor to the general difficulties encountered by investigators is that most of the cacti are to be found only far from the large cities in which the intereste lab orat ries are usually located. Ade uat classification of the mat rial is not easy, its gathering s ometi es hazard us, an the trans ortation flare no h an itie of mt ri 1 fr co lete studies a serious problem. Anot r fact or hi h mu t not b fo gotten is t et n ency o s o la h any iev o e due to th e or o s t e co oft e ants (ni ty to ninety-fiv er ) • r o i ed b t c ut o ities on acti, t on o ( ) , ho e n or on e 1 e 1, t o h e u e i e i n • .A. ( ) . n f o 0 0 on • 0 i ev d 11 ve c e, 1 r n m 0 e ve r h 36 c e d no i ~ K 1 i n O. In 1 4 ent fie 1 a drica. If e 1 i C n r f os i le in er st (7, , 9, o d an un- ac iv t n n o h o t he O n a: Opun ia ot on an e o re s of n a e f anch z' al aloi s wo k, th reduced • 4 to 1, 246 . It is not possible to state at this writing whether Sanchez ' discovery would invalidate the stat ments of previ us workers in the field regarding the ab ence of alkaloids in the Opuntia, as Opuntia cylindrica is, no with tan in its classification and in con ormity wit it nm d ste ed cactu. Most of the oth r e b o the rou are flat. out three months of wok a chemist for scr b d lkal h an lysis of on , it 1 e y t o vo at by th i antic l a or. t In gen ral, t ca tu al ka o n to 10 p c n r w i st n t ei h of he w 1 ht oft only n a O. t o.o r cen of al 0 C n C fr ly co 1 t u. 1 iel on t am s o alkalo d n c ry to con uct an c mi study w uld re uire either t e sage o on a pilo 1 n sc 1 or t do tion o r f n o micro met ods t u ou. I m t also be r me 0 ly e- f 1 0 ate ent se cro t t 1 h harma o lat t tudies are e ected to be c i 1, rela iv ly 1 rge uan i ie cted of the 5 l a t ter should be on .hand . A list of the investigated species and oft e alkaloids faun in them appears in Table I . Biochemists have been extremely inter sted in the structure of the cactus a kaloids bee us of t e rem· .rkable degree of uniformity to be found in the ubstances 1 o ted from t ese cacti th th ve been inve ti gate to dat. (8) . 'l'hi fact led several investiga or to dvance t ories of tne exi tence 01' a sin le biosynthetic proces at work t nr ug out t he c ctus f ·1y. In en r· 1 t h cc u alk - oi s c n e cl sified into two rou s . e r d riv tive of eit er phenyl t hylami es or 1 , 2,3,/4-tetrahy roi o .ui oli e . ev r'l ri c o sur c anism. ave b t 1 r e eriv· tion o t e tetr - y ino in r oup r o t corr i . 1 t l a - i e ._ . rier l ' ) i ~t 0 u sue . l. ~m . ccordin 0 i or t r e . l. orm 1 or C hyd • ctio . l. SC e (kno e. t n i C r n a 1 r a is ) wer e OS ly C ned . t con ition , U C t e r ur e c- t o r is co tio , ich C no occ r in 1 nt. 13 ) r r cently u t d a h t l di fe e t sche e, hich coul e ily e fol o ed r sor i o un y i olo ica co~ iti n . It i n o o l y 1 t e the compound just escribed ar er · cactus mily tat o be found . h 11 e w ich 6 TA L I Species lkaloids found Echinocactus williamsii Mescaline, anhalonine , pellotine anhalonidine, lopho_horine, anhalanine, anhalinine , -methylm scaline, Trichocereu c ndicans chlorus tetsoni coryn richocereu C chian -acetylme calin, 0- ethyl d- nh lonidine. Anh lin, can icine h 1 , c n icin Cor e n C Ca in, ricnoc rein ine ine C e 1 ( ) 7 was first faun . in Anhalonium fissuratum was subse uently d monstrated to be identic 1 with hordenine, previously iso lated from germinating barley. C rnegine , t he alk loid of Carnegia gigantea w a s .demonstrated to b i d ntical to s 1 o line which w s found in t he Rus ian Chenopodacea , lsola richteri. he great interest evoked by t cactus alkaloids was inly du tote str' nge and sp ctacul r allucin tions in- duced int users oft escal u t t ons ( ellot , o yo , peyotl) . T ef ect er irl accurately duplic ted y t a ini trc1tion of t h chi f alk laid m esc l ine at doses of about 200 nulli rams or or. It n s been u ed in riment 1 psyc i try becau o its a ility o pro uc i nor bject cert in t a t in to c i op r nia (14) . 'ti ic lit rature on t _ e su j c of t h e cc u 1 , Ql ou h u e voluminous , is r r poorl co-ordi at ~. inions a to th f ct~ o t v riou alkaloi ~ n ev ls t w ic these eff ct~ r r to be bserved if'f r i ely fr thor o ut or . In our studi s we ave iv sti ate a number of p cl mens of c cti obtained from th untin ton Cactus Gr n a ena . lt o h none alkaloids were isola t fro t ese plant~, a reviously descri e 1-aloid w found in an it erto uninvesti ate s ecie of c ctus. t etic ~ro ram w s t _ en i itiate -1th e no. of rep rin ome v riant o t e mescalin mol cul which · ht rov of 8 pharmacolo ical interest. This attempt was successful and beside~ a number of com ound which had been previously de scribed, two new synthetic compounds were produced. One of these cumpound was investi ated for pharmacodynamic activi ty. everal chemically unr lated but pharmacodynamically similar dru s were re-investigated under the rather suecial conditions of work adopted in our laboratory in order to be a 1 to make de uat com ri ons b twe nth action of tee et r known drugs and tho of the ne ly synt e ized c ound un r inve ti ation. CHAPTER I PR LIMI.NARY SURVEY In order to choos an adequate plant material for analysis a preliminary survey wa made of seven Trichocerii available at t he Huntington 'ar ens. Th e seven ecimens chosen at random will be found listed in Table II, to et er with t heir number in the Buntin ton Gardens cactu collec · on catalogu~. The test wer conducted int fol l owin fashi on: The material, consi ting of a cylindrical i c of t m of the cactu, a peeled, slice an f t er rok n do'Wl1 in a ~arin blendor in the pr senc of aqueous 1 er cent nydrocnloric acid solution. The product w filt r t - suction on a Buchner funnel overt ree or four pieces of filter paper on which a thick be of ecali aid) had been deposited . (a filt ring The clear fi trates wer divided into four te tube and the following reagents ad ed: firs t be, sodium iodide- iodine solution; second tube, r gendorff's a ent; t r tube Mayer's r agent ; fourt t ube, Nes 1 r's r agent . A 1 ft e tests performed wer positive, he only fer nee bein tat the Mayer's reag nt test was not as int nse and immediate i all case. Tr e rad of reactiviti wer Fresh Cata- W eight logue of rune of Cactus Numbertf' M aterial Tr. spa chi anus 5-99 63 gr. Tr. thalogonoides 15-22 1.30 gr. Tr. shikendamensi s 11-34 16.5 gr. Tr. thelegonus 44-25 25 gr. Tr. 11.UB. s cha Tr. lamprochloms 17-6 55 gr. Tr. candicans 17-9 56 gr. * Huntington Gardens cactus catalogue. TABLE II Amount of 1% HCL KI-I 160cc X 150cc X 50cc X 50cc X 50cc X 50cc X TESTS Dragendorff 1 s Mayer's Nessler 1 s Reagent Reagent Reagent X X X X - X X x- X X x- X X X X X X X ...., 0 11 arbitrarily designated for all reagents as x, x-, and-, x meaning immediate and heavy precipitate upon introduction of a few drops of reagent into the test solution, x- indicat ing an immediate but not as heavy a precipitate, - indicating a delayed turbidity taking up to a minute to appear. Table I shows the results of the tests and the amounts of material used in each, together with the amount of hydrochloric acid solution used. The differences of dilution ar due to the fact that the plants were not all of t he same de ree of turgidity and that in some cases it was necessary to add a larger amount of 1 per cent hydroc l oric acid o cilia e filtration of the homogenate. From the results oft ese t sts, and due tot act that Trichocereus spachianus was one of the mot abundantly represented species of Trichccereus i n tle ardens t 1 cactus was chosen as the material on which to conduct a complete investigation for alkaloids. CHAPTER II EXTRACTION OF AN AL-KALOI AL lJB TA.NC FROM TRICHOCERUS SPAC IANU AND IT ID TI~IC TION AL C ICI E About 25 kgm. of Trichocereus from the Huntington Gardens in Pasa na. collected and repared fore tr ction on e ne dl h ecim ns w re s e day. T e an eell r aration con isted in r movin t e ieces o cac us with a lmi ey w r ten ed 0 C ett wit . a co on kite nu e otatoe . T e ri r dd c ctus r 1 wa ten placed in are cov r er it ot o for r a nin. o w r 0 a rial . n J.70 lier of o w re dded . On i as star d and 2 .25 lit r of sou 11 er of fr t ol wer d . ept u daily or i days, tota of a tot trial and 12.0 1 tr in e iffer nc was r taine y t s r not r for ear of entrainin trial. T mat ria was k 1 u ally o d n 1 m. 0 1 e 0 o o n e ird y r in- oved ; r roce ure .7 i rained o • 1 an o er d t he coo, t e intenanc o ti 1 ve c n i in t 0 13 criterion for det rminin the uantity of fluid to be added daily after drainage. The 12.C liters of fluid wer e filt re and the fil trate was evaporated to dryness at reduced res ure (20-25 mm. Hg), the solution beings owly introduced by continuous flow into the boiler (15 liter capacity) of a large still. This boiler was immerse in ~ tr b th which was kept at a temperatur varyin between 30° d 5 ° C.; t r te t re n e e e. c 1 o n 1 n t • i V p w s tio 1 nt C t , at C 0 c ntr c ly la rin 1 e t t e jac ept at -5° C. t hr er e were t t e. 0 • 'l'he f i tile wt ve a 0 .6. 1' il br an t w an V 1 t ic d C r all ese e ro 11 1 ed . u • a wa i s i fil a i e d r t 1 s C n t C 1 i cop r - e t na o in e tak a co 00 00 • 0 i n 14 of pota sinm hydr xi de solution an brou ht to a pH o 9 . The solution immediately bee e turbi and a precipitate forme . This mi _ t re was immediatel y extr cted with e t her in a con tinuous extr ctio apparatus for a erio of s venty-two ours . The ether e act vap rate in vacuo yielded a mini 1 moun f br ·wni sh oil ic ave an alkaloi al re- act n wit o ine- ot s um iodides lutio after diss lvin in per c n c acid . T_ fr cti n, a di a i s f r any t er WO k . h t w,..s t n re ate for a ot her V nty- i d t ith c or • 0 ev po ti of c ri f n h r a a o n 0 r wn i w s fo n 1 • _ ft r C r C t 500c t h c ntai na t he en io wa cen 1 d . re i i t ft r r iz ti be in ic sal t 0 s i aluminum . h e n t luid wa C i~ie wi _ h r ch o ic Ci d e d t it r nwise ti no r 1 r i o e n iti n of r ea nt . T i a l itat w ten filtere off an was e on th is i l e • reel it t e was e t r wit trea 0 hy r o n i e . t th il r t e w s c ncent t e 1 vacuo, af r i "' i e r t liz OU in brilliant fla e s anc btai din . fas hion 1- • 1 as recrys 15 ized five times from 95 per cent ethanol and was found to melt at 128-30° C. uncorrected. This corresponds closely to the melting point given by L. Reti (8) for candicine, a quarternary ammonium base isolated by him from Trichocereus candicans. The extraction procedure<:! described by this author for candicine were similar to those used by us in the operations we have outlined above with Trichocereus ........ ......;..= __ u ____ s. An ly i of th substance isolated by u showed within th limit of exo riment l rror the sam e e .. co position a candicine. On th basis of th meltin and elemental compoition, as wel as t e ty ic 1 c tal oint ·cal beh vior of the quat rnary arm nium shown b the a o cone d that it is , - dihydroxy- - r methyl- eta- heny et ylamine an i t e candici e of L. Reti. C H Calculat .f r C11 Hl8 0 .I. 43.0 5.90 ound 4 .95 5.92 ical with An attempt wa made to re are the chlori e of the amine by r acting the iodide obtaired int ea o e mentioned rocedure with silver chloride. This reaction was conduced with water as a. solvent. Although r peated severa time, this procedure failed to yield any product, decomposition having taken place in each instance. 16 CHAPTER III. PREPARATIONS OF SUBSTANCES OF THE 3,4,5-TRIMETH OXYPHENYL GROUP Trimethylgallic acid. Trimethylgallic acid was prepared by t methyl tion of gallic acid (15). Eighty grams of sodium hydro ide an 50 gm. of gallic acid were dis olved in 500 cc. of tr in an atmosphere of methane. This operation was performed in a 1 liter 3-necked flask equipped with a mechanical stirr device and a thermometer. The entire as embly a kept in a crushed ice and sodium chloride bath. After the solution had cooled down to con tant temperature 89 gm. of d t y sulfate were added slowly un er constant tirri in uc a fa hion as to keep the temper tur of the 11 ui _ low ° C. Twenty minutes later another 89 gm. of th same sub ance re added in the same manner. Stirrin wa continued for ifteen minutes after all of the dimet yl sulfat ad en ad • Thi operation was re ated four times an t he re ulti products were pooled and refluxed fr two hour. i ty grams of sodium hydroxide were then added and refl in re sumed for two additional hours. Aft r coolin, t e crude trimethyl gallic acid wa precipitat d from t he resu tin solution by the addition of dilute hydrochloric aci solution. The precipitate was permitted to set le ov rni ht 18 in the ice box, filtered off the next morning and aft rs v eral washings on the filter with ice water dried in vacuo. Two hundred and twenty-seven grams of the chamois-colored acid were obtained in this fashion. This ro uct wa con sidered sufficiently pure to be used for furth r work without recrystalization. Thi entire rocedur w s also carried out on a ten times lar r cale with s tne same r sults. ially 3,4,;-trimethoxybenzoyl chloride. Thi sub tance w s pre ar d from trim t O"Y enzoic aci i two ba ic fa hions : (A ·t t . ony hloria nd (B) with phosphorus entac lori e. I e C ca 0 - di tions were varied o ew t from ate to 0 er to find conditions favori a tr yi 1 . o r on will be de cribed for eac re • (A) Preparation of th cyl c lori ~ h thion 1 c lo i Fifty-fur rams of trim t yl 190 cc. of enzene under r flu . ic ci w r e so 60 gm. of thionyl chloride w r- ad ed. A i olved in ion wa comp t 0 0 re- action en ued with the reduction of whit furn s . s he amount of fume iven off by the mi ture side 1 a once more refluxed. The r action a sto ed a tho 0 fuming wa still erce ti le after t re hour, an t e benzene and remainin thion 1 chloride wer d ti led off under re uce pressur (wat r um). U on cooli t e • 19 remnant solidified into a dark bro'Wl1 mass. This substance was then transferred to a C aisen flask and distilled in vacuo. 'his distillation was conducted at a pres ur of about one millimeter of mercury. The product distills at about 185° c. A yield of 22.7 gm. was obtained. (b) Preparation of the ~cyl chloride with hosphorus penta chloride. This compound was prepared by the method used in the synthesis of naphthoyl chloride (16), u ing 24.75 gram oft e acid and 24.20 grams of the phosphorus pentac loride. The distillate recovered at the end oft e procedure eighed 24.6 grams. 3,4 1 2-~ri~ethoxybenzal~hyde. This compound wa pr pared b t e Rosenmun reduc ion, an operation consisting es~ential yin t _ r due ion of he acyl chloride to the aldehyde in resence of a pa ladium catalyst poisoned in such a fa hion a to revent the re- action from proceeding beyond this point. me authors have apparently encountered such un urrnountable d fficu ties in setting up this reaction tha they promptly abandoned it for some alternat method, while others have found i ex- cellent. Our experience with the reaction ha een t _ at the important factors are the mechanical ones and tat unl ess tbey are most care!u l y controlled t e yie s promptly fall to zero. These conditions have been thorou ly descried 1n 20 the literature (17. We must add that the use of am rcury sealed stirring device ha been found im ractical by u be cause at the speeds at wlich the stirring ropeller has to be rotated in order to insur ad quate yi lds mercury splashing is unavoidable . Ye used a ecis on- round al glass tir ·ng shaft nd joint and f ound t 1 as embly to b ractically leak r oof . cyl c loride er found o r cti on as t th size o t y 1 of a bate . The atche of aroun 30 gm. o t e the e f y e r o r s o t on y c ti uo upo in r · fie 1 a tion was ma ur m nt c ec ed t roug ou th o r of t h hy roe loric ac d ro ed ( 7) . As UC s er cent oft or cal un o t volv d r action was r cov r d inc r a r s . 0 t e i h ydroc loric i y ra al 1 d n v r roe 7 c nt, mot o t en around e r er cent . T separ tin o tion xt a olu ion fro w t e cat ly t ha a saturat ol tion of sodium bisu fi ce 0 0 rni , and fi l teri g off t e ale ye fr m 1 en f the x.yl c r f e, coolin in t e it er stall ine a dit- ion ro u • Thi whit cryst lline substance was then re- olve in wat r and aft r fi tr tion a dilute hydro- C oric cid solution was ad ed until n further reci ita- on co 1 ob erved. The oily r ci itate lras left in 21 the ice box overnight. The next morn g the recipitat had completely crystallized and was filtered off. After drying, this white crystalline compound, 3,4,5-trimethoxybenzalde yde wa found to have a faint floral odor. It melted at 76° C. 3,4,5-trimethoxy-omega-ni r ostyrene . A r viously publi h method (18 for the r ar tion oft non-substituted nitro compound were follo wit al owance fort iffer nee in mol cular wei ht . Te 1 e yd was cond n ed w·t nitromethane in he re ence f sodium ydr ox de, th so er tion bein carri d out w t h th r action ves el i er ed in a rin ba. hi or er o ke the mi tur be ow 5° C. all time. T e yie d in var ou ba c vari db t en 63 er cent nd 9 er cen o t eory. m a V our m e tin 0 c. r na d in ri ty elve reaction fferent a --- r n y oin oft e co oun was f ound to be be 1 een 120° • . ion f 3, , 5- rimet oxy-o . ega-ni ro ne. y ro ion of t s nitro com oun en a numb by sev ral earlier r s . u of roducts hav be en obtained bot by o ers and a a r sul of thi operation. T e a r of t e e ex re ly d n on t e condit on , widel en ro u ts can be par d n t i react·on b . or var ation in techni ue • In t or ina 22 synt esis of mescaline by spgth (4), thi author reduced tte nitrostyrene to the oxime in a zinc and acetic cid mixture . T obtain the amine he furt er reduced thi com ound wit sodium amalgam and acetic acid mixture . If re uced with latinum black in methanol in a standard hydro enation vessel th compound dimerizes 1th the u take of one mol o hydro n. Th two di er s obt ined inti fa hion ar i o rs and ar 1,4-dinitro- ,3-di-( rime oxy en 1) an ,3-din tr -1,4- i-( i etho yphe yl) tan , t tion havin occurre at the doubl ond . WO il r 0 , i w ic t 0 henyl rou s ar 4, - len u r ar d i the s fa ion 0 C r (19 • ini 0 co oun h s been rt er d o n d o t e a , · ne . If h ro e a ion is C r d o i • 0 on a ales an ac C • on l. u a olv a s condar amin urther descri ed as C i o tained. If s lfuric id i add ri z - 0 d r i 0 C aci 0 r tion m SC l in i ro uced. i :ne i i • nitr Thr in n tane w r o a e a i ar h r 1 co - 23 taining 55 cc . of absolute ethanol . The flask was cleared of air by evacuation and connect d to an hydr gen- cot i in gasomet r . The flask was shaken until no furth r uptake of hydrogen could be noted . It required 170 cc . of hydrogen to saturate the cata yst . At this point 15 gm. oft nit o- styrene were added , the apparatus re-evac at an r co cted to the gasometer. Shaking was resumed for a period of twenty fur hours . At this time there was no lon ran nerce ti 1 nydrogen u ta e d the tota amo t 0 as se was 7 0 C • - e theoretical u t e f r this o ... e t· o ave e 710 cc . Te r maining 70 cc. of .. ydro en were pro 1 ke up by a certain amo t of he om und w h ·ch w e UC d b - on1 t e e ecte oint . T e r ac ve s 1 s no wit a rayis us n io which wa r ·1t r edo • T lect mat ri 1 0 the filter w s then washed i ha lite of a ixt re of et ol d ethyl ether in r The original fi l trat an t e wash liqui were eva or t et er in vac o - and 2 . 5 m. f a la y re id- b- st ce was left as a resi e . This fracti n w r h • vesti ated • 1 The rays bst ce left on t e filt r d c m or anic t r · a s lv di boi i i ed it pent lati um b cetic cid an se arat r o a s i - h ata ys by hot filtrati n . T r ecove e cat 1st a e 0 • 24 moved from the filter and weighed after drying. It was found to weigh 2 . 47 gm., and since only 0 . 75 gm . of catalyst ere used the balance of the weight was made u by some other subst nee or substances w ich wer not rt er nalyzed. The hot filtrate wa subjected to ractional er tallization fr aceto wei hed 3. 35 gm. (fraction A) an • 55 m. (fr cti n B) • The c mpound k 1 u 1 no ive sh r lt oi t t at 1 oo C., si at 0 melte 0 0 nd 0 c. 03 c., an twe n c. a hoe t ' fo 1 wi r es lt • Fr ct·on A. C Cal t 0 C22 28 °10 2 4.9 • Foun • 5.10 • 11, C p t Fracti n B Ca c C22 Found. oat e t p ds w te for 0 10 2 were ic w ti n of t e 0 it on y evidence ed ·nt was a e on th ose re re by onn C • 9 • • 78 to ynt z the e t·v so have r t t ons of t e ze in arrivi at CO C 0 n similarit b tw e t J. s 0 chellen er ( 9). he e • • 6 / • .01 e s . d a t or 25 prepared the non-substituted and the 3,4- methy ene ioxy substituted analogues from nitrostyrene and 3,4- met ylene dioxnitrostyrene. They found t1at tne two least so uble isomers were the ones in which the phenyl groups were sub stituted on the second and third carbon atom of the chain. The structures of these dinitro compounds were proven by their oxidation to the correspo ding substituted succinic acids. The compound cons ti tu ting t: A fr · ctio- of r re - aration and assumed by us on thi b is to v nyl groups substituted on the second and thi c rbon to of the chain is insoluble in most of the organic oven save slightly 1n acetone and relatively e sily in o 1 cia acetic acid. 2,3-di-(3 1 4&5-trimet· oxy) put~eseine. The dinitro co pound de cribe a fr ct n lieved to be the 2,3-phenyl-su titute ism r w t !'ler hydrogenated to t..~e corresponding diamine. An o i ry hydrogenation duck was used for this o er ti • it s il l e with 50 cc. of acetic acid and 5 cc. of cone tr t ri acid. The catalyst, 2 gm. o platinum 1 c was en in- tr duced into the apparatus and ydr ge_ te in th u 1 manner. After saturation of the cat lyst wa co ete 3. 3 gm. of the di itro compound were introduce int t ve sel and after evacuation of the latter hydrogenati n was rs The uptake of gas was exceedingly sl wan after ninety- ne • 26 hours of sh king only 830 cc. of hydrogen had been taken u. t tis stage the hydrogenation was int rru ted. Theor etica l y, the uptake should hav been 937.5 cc. he contents of the ves el were filtered on a sint re la filt r ft r dilution to 100 cc. wit lacial cetic cid an rin ing to a boil . 1 1 e filtrat w reduc d to dryness in vacuo aft r neutr lization oft r ai n ulfuric aci it a corr ond n mount of sod um h dr o id. ial co 1 b i olat d b f r f 1 r w fi l r i on 0 ho o "W i ~u. f l coho 7 m . of f ollo · ce a C u dr. t i t o 0 c •. s - d: y r r C r , C r o 0 it r o C oi i V CUO 0 C o a ic m t er i fract· o . t r n tr . ft V er C a CO C -( 3, , 0 • t 0 i- 0 ov r- 1 • Cal culated for (c 11 H 16 o 3 N) 2 H 2 o 4 4H 2 0 Found C 44 .73 44-75% H 7 .16;o 6. 870') 27 N 4-74% 4.76 ft er rying to con t--nt wei ht in vacuo over phos horus entoxide at 80° c. th cryst ls lost mol cules o w t r and analysis sho ed: C N Calculat for (C l 16 03 ) H20 4 • 0 6. 80 . 5.1 Found 7 . 33, 6 . . 1 ucc 1 d to is C in y t e ir C en oft i r 0 s s een t t ove y tt ic r UC t r co h 1 r 1 i n e 0 0 0 t ro uctio of h two alr de cri e r • in t ex sive f icultly t 3, J - et ro t 1· ne . l i s t e 1 1 r a wit t o ue . . rt r -o formed V r r s , so e o t . em e err fo r ec anical r a ons . r acti odi . ., er 1 i e duri g thi ti i t t to . r ov i perform ce. • V- 28 The vessel will be described in its final form and on typi cal run onl y will be outlined . The vessel consisted of a cylindrical hydro enati n camber, 19 cm. in length and 6 cm. in diameter. T 1 re- ce tacle ha three o en s. The fir toe in, used for filling and emptying, was e uipped with a 24/40 tand r taper female h lf-joint . T e mal art which erved a a plug was sealed to a 4 mm. to cock, the two rt 0 t e joint havin glass horn in or r to r it the of springs. T e s condo n n a al t o r o - pin funne e ui pe w th a 4 mm. to cock. t r 0 n- ing, which served a ave t t h r sure in the rts of the y t m, w n ealed to a len th of 8 mm. tu in fte hav n curved b c 1 in uitabl way r t b c in t e y 0 o e bulb o th dr ppin unne • U t e s gl a to ma i i ea p ritie wer seale in ossible t st etch a len c v red re i tan r t • he arre o c ntrollin the flow from ~e dro 1 funnel he C to t h cylindrical came and int e pl ne o t e moti n. y other o ition oft i t cock reatl en thew ole exp ri ecaus t ... V modi po iti n of th st c ck core, thu 1 any accurat b 30 hi coc f e r Plate No. 1 Hydrogenation Duck 29 tin impossible. Both stopcocks were equipped with tighten ing devices in order to insure t maintenance of their settings during shaking. The upper part of the dro ping funnel was connect d to the gasometer. (A hoto raph of the device 1s inclu ed in the text.) In use, the bulb of th ro in funnel wa filled wit a ot so uti n of the nitrostyrene in 1 ci 1 ac tic aci . u n in f alladi 1 c- n 1 cial cetic ci an co ntrat sulfuric ac a our e y ro enat on chamber . As ow h r o hen a r ctly fro a co t f 1 C h a t exi h C in . Ate a 0 0 and t h pr v C 1 n f • t b en fille t hi o bub was conne ya v ria r t two n a t nt a o m ann r t h ulb wa of V ro en fro C 1 e t y insol b ni ro tyrene e c k 0 - on 1 n ro r t ~l zin ou of so t n. T s ._-.U•.J.n a hen ted t r pi f el st co k A am un 0 roe ct ly t which un er th con io s d scr· e a 11 30 found to be saturated in about twenty minutes . After sto ing the device and taking a reading in order to determine t he amount of gas taken up by the catalyst the sto cock was o ened and set so as to permit one drop oft e warm solution in the bulb to dro every secon into the hydro enation com- p rtment. The hakin was then r um • Th o erat on wa usually completed in about an hour. In one ty ·cal run 5 gm. o n·t o tyr n were di - s ved in 65 cc. of b ilin lacial ace ·c aci and our d into the dro in funnel. Two rams of palladi m black prepared followin t e et od of illst t in ro UC d i t t e c lindrical ydro enat on rand 0 cc. of glaci 1 cet c aci f "'re b cc. concen t e ic acid were poured in. The c t lyst a t n ro • 'l'wo undred cubic c ntimeters of y ro en w re u d n is o erati n which took twenty minu • ydro e ation o t e nitro co oun w in iate s mo en in th fas ion des ribe bov • Int i instan e t e op rati n a com- pleted in forty-seven . ut s. Th eor ti a ak of in tis cases oul have b n l .S7 it r; 1. 60 1 t rs were actually se. Aft r i s c ecting t e a ar tus, t e con 0 the r cti n chamber ere emptie int a s red lass C er ilter an t J. set ct lY.st senarated ... from the fl i art 31 of the reaction mixture . As ra idly as po sible a solution of 7. 6 gm. of sodium hydroxide in 15 cc. of water were ad ed to the filtrate in order ton utralize the sulfuric cid present . The sodium sulfate formed was a lo ed to ettle overnight in the icebox and fter filtration the next day the filtrate was eva orated t dryn s, in vacuo . The residue after dispersion in a minim 1 amount of wate was poured int a co ti uou e tr ctr fol owe b twic it volume of 50 per cent so ium hydro i e o u ion. ether with ihich the extra t·on a p rforme wa and after settin u the a paratus in the usual fa hi nit was permitted to run for tw nty-four hours. t the t er hase wa collect over sodi lfat b re and r sin a 0 earn o eve a h ry ri ac c loric aci (ga) t ou hit. The h y roe c used a white prec pitat to form whi a col a sintered gla filter and rie in vacu over entoxide. After t re recr t 11 at n a co r o- on 1 et er thi reci itate wei hed 1. gm. an melt d at 18J 0 c. Calcul ted for C 1H 18 03NCl Found C 53.33% 53.56 H 7.32 In the rocess of recrysta lizin t em sea in hy r o- chloride a small amount of another sub tanc e wa isolated which after being purified by t he same process melte t 244-5° C. with brown -black decom osition startin at • 1 e crystals obtained from bsolute ethyl alcohol solution are in the form of small pl tes which when he ted on t he me ing point stage changed into needles at around 227-30° C. This subst n is a olym rph . T 1 secon ry ami·1 wa r are int e arne ap- paratus as mesc 11 e itsel , t eon y variati n . ein t lfur· c he r en is e i e ic t ote from i i a C t th ed tote cial cetic • C in h 0 32 trea r i n u i ic oul i ga • a s s u·t d r V r e o r r t iz ur e o f tio . e i r t 0 1 h rm ic 1 iv ti a h i s a s l 0 of er C id u in n al i ' tio a he t of cru e it a carrie li tin rs ure o micro g, t e oo ' s mt t 1 in tea ara- t s i1 1 ept at 200° • The li tion as lo , six to ten hours bein necessary to collect 1 gm. of sublimate . After two recrystallizations from a mixture of absolute ethyl ether and absolut et anal the colorless com- ound melted at 223-224° C. Calculated for C22 32 06 N Cl Foun C 59 . 78 59.5 N J.16 .J6% Cl 8. 02% .o 33 T v ra er iel of t s ub tanc wa 32 r c nt of theory. ur n th r s f recryst izin t is com oun mal 0 of er stallin ub C wa isol t fro them er 1· uors w C aft r be n cted t tal- liza melted at 17 -90 c. . tanc l. w no urt at roi C h e . 1 Oi- of view. r d uctu e 1 C i i e . l. • 1 C APTER IV. t tem ts were m· de to pr pr so e other a alo es of phenylethyl a ine for subsequent harm colo ical investi · tion . Only one f these · tte~ ts as successful . e others failed t v ryin step oft eir s nthes i . _ o o i er nyl- ine re in ood ield from hel tro in . he ucce ful pr ion were t e f ollo win .. : D- .,; thoxy_ e y- e i s ldeh e · ' 3, 4-m t hylen dio y-5- .. t fro .yri tici • 3- -4- le t e fr V n · ' 3, 1 t yl fro V l i r 1 yl ,t yl ine fr C . l. hy e . , - t yle i a-nitr tyrene V t e of' C m erci 1 i (3 , 4-methyl e- i xy e y ) .. er C e se ith rom t ane the t cri ed r th ynt is o 3, 4, 5- tr n t o ga-1 r styr ne fro t e corres o di al ehy e . overal iel of 84 pr cent w a obt i e T . co:n un • 1<" ecr s 1 ize nee r laci 1 cetic Cid b fore f t her use . 35 3,4-methylenedioxyphenylethyl amine. This substance was prepared from the i eronalnitro styrene just described in the same app ratus and in the same way as mesca ine. Th yields owev r were much be t ter than those of the l atter as the over-all yield amounte to 63 per cent. The white crystall ine product, recrystallized from ethanil, melted at 210° c. Calculated for c9 12 Or Cl ound C 53 .4 53.2 H 5.98% 5.82% N CHAPT V XPE I MF' T L PH R CO LO GY The ~ork that will be descrlbed i n t hi s ction w erformed in or er to evaluate t ne biolo ic l e ct of one of the hitherto unknown synthetics st nce s p e re us . Thi s co po1..m is -I-me calylmes c i ne . he Jdrochlori e of ti s second ry ami _ e whos pr tion e cribe in other art of this t esi s u e tr u hou e ha.r mo cological i nve ti tion . 1r . l eren t ypes of biolo ical re r tion w re u ed . T e ne ru w t st on t ane t tise r t ' s blood pressur on . al , l mall i n t tine , d on t he driv • ol l e strip of th rat · ' it a l o re 0 mic in or er to et r . e it· to icity. Int _ cour e o t h e i ve ti i n j s e i _ ru s ot er t h 91 i t i st ce r r on lo e i or ur os r i conjunction con ri on . T sed r ri , rt re ol , 0 n t rtrate , ne , ac tylc olin , an ib n mi • ine u e i 11 o t e r ar i on , an the other drug -er used i t e b ood pr s ur e perim nt . e i cro~"'1.al ti ca or- d n in or r to rove t structur o t h roe lori e, t e arbitr ary si nati n 0- 91 a iv n i • his na · 11 r e n i i C in 1or s a 0 r vi • , C HAPT R VI EFFECTS OF 0-291 AND OTHER DRUGS o TH , BLOOD PR 1 S U R · o THE RAT In t hese experiments male albino rats weighing as near as possible to 300 gm. were u ed throughout . They wer anest etized by intraperito eal injection 1th r ith commerci 1 Vet rinary embutal , solution of pento r it 1 sodium (Ab ott) or with a 20 per c nt solution o u t h n. The use of the pentobar ital olu i on wa abandone it early in th ork as it prove to be too toxic. n t 1 r co en ed used the anim of d pr s i o cc . er 5 o of boy w i t) w C ose · r of esi w r ur e y ...- C let 0 survive , ow v , 1 g ro sy e wit s OU t r i for n v r ctory unti t e C e lly i • ' f f Tne ff ctiv total os of his r p r tion fo tween cc . n . .., cc. used w . f o d o of o y ei ht . r t ane rov . 0 1 an ic . O u r c nt l u on of r h • f r t V 1 If 1 ent . i · f c or inj ct c 1 y t t 0 0 cc . e km. (1 m. er in r p ri o . ) in uce ur ical ane t i . · a j o ity o t h im ls i t n i or 1 • In ... fe d i on 1 s 38 amounts of _ uan 1 tie estletic had to b a mini s t .re ut n .ver in bov 0 . 5 cc . of t he O per cent olution . fter . s tisf ctory lev 1 of anes he ia w~s r c ed t r at c'"roti hy h 0 C i o 0 0 l a i 0 0 C V i • r attache to a bo rd an ur ery t arte- . The rt ry w xpo ed and cannul i n 1 - t co r . i dl ; O. ✓ cc . of one pr cent solution of inj ct ct d o t _ rou h t h ee • e dl i 4/ O OU f" i r OS 0 ir C cri 1 0 • • C 0 - rri i d ' o e i 0 0 a o i- 1 od 20), 0 - 0 ' 0 i o , a r n 0 • i i g d o i t C - 1 v r ·· r co C as e p i 1 fo ec ue o h (20) r 39 was found impractical by us as a con ider ble amount of the fluid injected was lost throu h th branches of the jugular vein which had been sev red durin surgery. In one ex eri rnent the abdominal aorta wa cannul ted. Tis r ctice of course makes the o enin of t h e dorninal cavity neces s ry, inflicting undesira le trauma. The administration of 0-2 1 int untr t d animal and in the rat which has r ceiv don or ev r r vious injection of i e. ri e t a do 1 v of 3.3 e km. r o c d un re ic t r ure. In , in o est e i a oc u s C n i y an t en it w .3 1 er c.. mgm. t 1 1 0 e . , nt of d se. soluti n er t i l h e th C • ction r 1 . no in C t e r C tha if O n of c le 1 ro • ne o t C n t t fi . 0 re a n r ev ccoun • r vio ur n vi i or of 1 t h e It n i l y OC n s or r v r a o e r f c e. n i o t e lood res.ur (fi. ). It a pos i le to lock the ffect of a many as five succ ssiv ose of 6.6 gamma per kgm . of e i ne rine over erio of more t han an hour m. of 0- 91 . A o e of 40 3. 3 mgm. ner kgm. of 0-291 was foun to b a e u t i n all C es 0 loc t h res or f ect o r t i_1 i ... tr ti n of 3 . 3 r m. of 1 ep ri e . i feet was f ol- low for out tr an h 1 our t e 101 e. to rv - tion . It n otic t i 0 V on y 1 C C d i o t 0 0 r . 33 e i 0 0 0 0 0 iv il U 0 • 1 t 0 u 0 e a • so 0 • ol lo ,. 3 • ..., 0- • oc C e ) . • 0 0 1 n or u e Ol. 1 C 1 e 1 • r g 1 h l i 1 d V u i o 0~ 1 ( i • 3) . 41 The depressor effect of acetylcholine wa otenti ted by previous treatment with 3.3 mgm. per kgm . of 0-291 . Tis potentiation coul be demonstrat din two w ys . Li i 1 doses of acetylcholine (0.033 gamm per kgm.) which cause barely perceptible drop in blood r ssure w hen injecte before 0-291, caused a well-define dro wh n i j c ft r 3.3 mgm. of the potent! tin ent (fig.~). ell- rked rop in loo res ur such as those ro uced by the in j .ction of do es of c rlc oline o · th ore o 0 . 3 a r kgm . wer otenti ted about fiv times y t r viou in ection of 3. 3 gm. r gm . o 0- 9 fi • ) . re of otentia on v t e de re ion on t ju tr· in . 1 r in occurr nc tee exp riments an r ferre to a, d f ur o d u r -out" . _ en afte inj c in of 3. 3 m • o 0- a loci cul b demon to . 3 r • o ti lock cu ir 1 r v i jec 1 of s ive s o e • er . ) . ft r t e normous rise in bloo r ure which fol o e c inj cti n a sub i e , the 1 1 f o one ct. ct , r su c ti le tot small dose (3.3 amm pr k .) to w ich it a become un active (fi • 6) . f rt 1 - tr ion o t am aunt o~ - 91 once more blocke ffect of th s -11 do of epine ine. is "w hi -out" 42 of the blockin agent coul be repeated a many ti as d sired without app rent mo ification of the results . In one experiment 3 . 3 mgm. per kgm. of 0- 291 an 3 . 3 gamm per kgm . of epin phrine w r injecte simultaneo y . Jo c an in the blood pres ure was evidenced . 'l'Wo bloo ressur experim nt~ er run to s y th eff cts o dibenamine on t e rat for of comp rison it1 0-291 a nod ta re vai en ine on t i im • Di en 1 on t ec s o se i do s 0- 91 in t riment fift minu r vious ex rim nt . I t e el psed for t he f ec ini t .r di n i C r eriod of im 4 i j ction of ri (3 . 3 m. ) C U 00 pr j c i on of epi ri 0 0 r e (fi • 7) . ~ V i u r 1 f rst evi nc d i j cti f 0. 3 • e i dmi i r , r e l oo r d . In t r e r U C s m co ditions t 1 C in f ec 5 0 t nut aft r . i i o i ine . 1 r 0 er k m. ) loc e 3 • ., • k • ib n e. c tylc oline n o e iate fee i en e y i el . ica • 1 OS e s arp transient drop in blood res ure . i- m first 0 C ur iv r nol of f- C U 43 Ergotamine tartrate when injected by itself caused a drop in the blood pressure of the rat when ad.mini tered at the dose of 1.5 mgm. per kgm. This same dose w s imme i te ly able in one experiment to block and in another to reverse the effect of a 3.3 gamma per kgm. dose of epine_hrine and that of an 0.1 mgm. per kgm. dose of art rEnol(fig . 8) . These effects continued in each case for a period of an our aft r which the experiments ere iscontinued. The de res or effect of acetylcnoline re ained un lt red. CHAPTER VII THE FF CT OF 0-291 0~ TE RAT'S ISOLATE The universally used and tandardized gnus sooth u scle t chni ue w s used in this investigation. he bath a 50 cc. ca city and ollmann nd demaeker's solu- tion wa u ed throughout. In ractice on y 40 cc. of olution ere u e in the at an t re lt of th tests 111 b ex. rs ed i mm. of ru 1 tro uced t ti amount of fluid. m 1 no t t . t o 1 1 t t 0 concentr tion ., 0- 91 t 0 tine, 1 n , W C f t n e i e rin r axa io ro c as y t a i one tot atly r uc T ff ct o 1 m • o , 0.1 m 0- 91 tri, di s 0 t r co oun • of e i rin f • 0). t lo v d with 0.05 mgm. varie f e t ) . 1 of r C C from 0.01 u. o h t en c dr t 1 ton or u lock • same f ect a c 1 ~-. -.... • of ru • r c nc n r ion r tions the in rin nd of epinephr" e he in ffect w o co € u r ax ti a re uce to out fourth of its liner v lue int econ- trols (fig. 11). 0-291 reduced the surface area above the depressions evidenced on the tracings u on d ition of epinephrine to the bath, by a factor of about 25 . In this case the dur tion of the relaxation is taken into c t . 45 A general observation in this series of te t was that after the administr tion of 0-291, e ine hrine no longer inhibited the s ontaneous contractions oft es ri, even wen the lengt of the strip w s incr ased by the pressant effect o the latter. CHAPTER VIII TOXICITY OF 0- 291 I ~IC ine ice were inje cted intrav nously trough the tail veins with solution s of 0-291 in saline of increasing concentr tions . These ani ls wei he between 10 and 20 gm. Te axim 1 amount of solution injected i nto any one of the ice w 0. 3 cc . ne anim 1 were e t un er observ tion for everal wee after the a ini stratio ft e drug . One o t e ani ls s c pe t hree d s aft rte injection not recovered . ot er et in 1 s s jar died of what eeme:i t be c u s ot e t ef ect oft rug ur da r i jecti n· it p n r 1 until ten . o n 1 r i ected at 0 e V 1 . 11 0 ls . t i ri vive t a tr tion f t without tect- 1 effect t 0 v r eit er i . for of ons . · .. jected e avior or 0 r e , o, 100, 50 , 330 , 400 , 500 mgm. er k • e r ceiv inj ection of ach do e ce t or the 0 er kgm . do e w ich w ad.mi istere "' to 3 • 1 _ 11 l • urvive • T e V 1 0 th 0 dos e C no t V the 0 gm. er k • 1 vel becau e i i i le to di 0 V 1 r r aunt o t e substance in the o. cc . 0 ti s siz s l i ol i on C 0 C fely 47 ad inister to mice. The reason why larger groups of animals were not used in order to obtain more si nificant evidence is that it was not deemed wise to use up the extremely small stores of the drug remaining in the laboratory. CHAPTER IX EFFECT OF 0-291 0~ T DRIVEf ISOLATED RAT' V r T ICL , T IP The series of experiments described in this chapter were performed with a preparation erfected by r. George Feigen oft is department. A strip of tissue from the right ventricle of a rat's heart is made to contract isometrically 11 oxygenated bath. The untreated strip i s m a e to con tract by 1 pulses enerated b an electronic stimulator which ermits both the rate and otential of these i m pulses to b ccur t ly controlled. Te strin wil, w·thin l i m·t, follow t e bet o t e sti~ulator. The rat and am litude o the resu t· co tr ctions can be a ured or recorded u oto raphically a r am lifie by l i ht lever system. h fi r t twill be iven ar ex resi n of t e fi 1 co centr tions of t he twos b tanc s use, 0-~91 and e ine rine, int ecial olu in erfected by r. _ ei n for thi U OS• A concen ration f 1/1 0 ,000 o - 91 ha no f ect on the litude of the contraction o the riven stri an does ot ch it ability to fo l ow t . i ul se r a e of t e tL,ru ator. A concentration of 1/1, 000 , 000 of e. ·ne. hri e in u ce s S 0 u s co r ctions of irre 1 r na t u r e i n t e r ep- ... . 49 aration . Concentrations of 1/100,000 of this substance cause regular, sustained, and rapid spontaneous contractions sug gesting fibrillation. If a 1/100 ;000 concentration of 0-291 is nresent in the bath before the epinephrine is added , the spontaneous c ntractions do not take place upon the admi istr tion of t e uantities of e ineuhrine mentioned above . If at this ... oint t he stri is ti ul te electric lly fi rillation is i uced but l asts only about one-fifth to one-fourth of the tie tat it la ts in the unprotecte un timulated prep ra tion . in t h ore r o e cally t fter bat ctiv oc hin out the dru sand can in the soluti n t e strip returns t its former stat an is once toe ine hr·ne in th fashion descr· ed . T s can r peated on t sa e strip ,1th i denti- me result. i o ex riment of t _ is type t en · ht e sa r sults . r un er- C tiAP'I'BR X DI CU SIOl The structure ascribed to 0-291 in thi thesis (N-mescalylmescaline) is based ri_ arily on t e results o elementa analysis . ltho gh t he values found for c rbon, hydrogen, nitrogen, and chlorine corr s onde ily with those calculated for -mesc lylm sc ti s ctor , t y re also uite close to those calculat for 1-(3 , 4',5'- trimethoxybenzyl)-6 , 7, 8-tri etho y-1 , ,3, - tra ro o- auin lie hy roe loride. is o ntion o u ces ound in re, no coul e e on t 1 a i of ic 1 co ve t r ydroi so ui oli a he e IJ -mesc lylme c i n V r t f ct cont i . 1 ro en a oms. l t t nalysi corr e on mor ..., clo e Y . t t l t r e f ic . ent t t he r e t 1 ti to C it er s ctur. t h of 3.3 mm. ea or f c ive bloc i en for th or er o • a r • an ib C i o t . T r C 1 0 orm r V C 0 1 OU h to ic do co 1 no se 0 r- 51 tained, it was found that the highest non-toxic dose (500 mm . per 1rgm.) wa such that at the present tim we can af ly conclude that its t hera eutic index is well bove 100. o comparison can b mad with dibenamine s the 1 thal o e of this compound as not been ublishe for rte. other characteristic of 0- 91 nots r d b ibe namin i its acetycholine-. o ntiatin f ct on ood pres ur. The f ct t t 0-~91 lso nt o i i ry ri eon t e r at' isol t d v ic i ~ s al i tine sug t tat it 1 n S 0 i ri e s 1 ve I ot r ve n ve o ct o o , as 0 0 o d 0., • O Ci ·c re (21). r t i e 1 i p i go p r ps ce ot nti ti o 1 d s i • t 0 r 0 oc C 0 1 SUMMARY 1. ecies of Tr . choc w r i . a t even s r us V l. or lkaloi dal content . 11 were foun to co tain lk - loids . 2 . Four of t he above entio ed s ci e , ely, Tr. . Tr. t nalogonoid r. spac 1.anus, r . - - huascha er not r viousl 0 0 co n 3. An lk loi i • ted t candici e , co 0 r s exi s in _r . C • 1 1 ·• our i , o- , .,; - i-( i , 3, , r· m 0 h ( ,, , .,, - r ) u , 0 • ~ 1 0 0 • 0 r a ' n , • 6 . C 0 ,. C 0 0 • • S C SC i 0 0 00 r- , • • 0 i 1 C • F 'igure 1 pine hrine r ver a with 0-~ e 2 QC 0 Fi u e .3 ot n e ec o O 9 on 0 s e es on. - ,. '1 ur 4 ot 0 0 0 0 Figure 5 Po n f ce 0 e 0- 9 ur igur r'i ure 8 A enol e ·n n r ine ver a 0- 9 5 .. '\ '{).:,~ c ~ Y, I 1· J O. ,; 'i gure 1 / .0 C I.: f> f ' 0 .. ()0 . ~<"<: ~ M.-sc., ~1 11 f Ht/ (). z o/. I p1nephrine antagonism of 0-291 on gut w /. 0 cc. Ept' J : I tJ, l' " ., " ~~-. ,,~ . f- HT I l j eJ"ltNIAM 0.5<t. W £ ,,,. / • I• .- • I Figure 11 ., ./f11WJ1 u '(l • e a ,,,., W .,.,eh ,..,.___ t •• o.s,, 1~------ M•~C #2 o.e. ¾ \ . .. IV\ "\ 0 .s--'-c. ~ . -·· '~ ,,, ,o Incomplete blocking or large doses or epinephrine by 0-291 in the rat's small intestine 64 BIBLIOGRA HY 1. Lewin, L. Arch. Exper. Pathol. Pharmakol., 2~, 401 (1888); l!, 374 (1894). 2. Heffter, A., Arch. ,Ref. Eathol. Pharmakol., .14, 82 (1894); 12 65 (1895), /;;2., 3 5 1898); Ber., 21., 2975; ll, 216 (18%~; 1193 (1898); ..Jlt 3004 (1901); Heffter A., and Cappellmann, Ber., l§, 3634 (1905). 3. Kauder, L., Arch Pharmaz. y. Ber. Dtsch. _h· r _ . Ges., 237, 190 (1899). 4. Spath, E., Monatsh. Chem. A.Q, 129 (1919); A:l.., 97, 263 (1921); il, 477 (1922); .22, 141 (1933) ; Ber.,:M, 1778 (1932); fil, 266, 2100 (1934); ~, 755 (1936}; path, • and Gangel, J., ~on~tsh. Chem., !dz., 103 (19· 3); path ~. an Kuffner F., Ber., 62 2242 (1929); Spath • an Pasal J., Ber., 62, 1021 (1929); 1 path E. and oder, H., ~onatsh. Chem., ill, 93 (1922); path E. and Becke, Monatsh. Chem., M, 327 {1935); Ber., 68, 501, 944, (1935); Spath , • and Bruch, Ber., 1Q, 2446 TT937); 11~ 1275 (1938); path ., nd Ketsszlter, Ber., M, 1663 ll935J. 5. Britton, .L., and Rose, J .N., The Cactaceae, 4 volumes, The Carnegie Institution, T ashington. 6. Hi gins, ~. B., Our Native acti, e are , New York. 7. (1928). eyl, G., ArcJ!. Phar., m, 451 (lg l); 266, 668 8. Reti, L., Rev. oc. trg. Biol., i, 344 (19 J) ; Anales Asoc. 2uiJ!. Arg. ~, 26 1935); Atti _., Congr. Intei:naz. Chim., i, 396 (Roma 1939); Ret, L. an rnolt , R.I., Actas V. ~ongr. ac. Med. J (Rosario 1934) ; ti,~-, Arnol t, .K. I., and L uctuena ., ~ -.P., Rev. oc. Arg. iol • ., 10, 437 (1934). 9. Herrero, Ducloux E., Rev. Rae . Cienc. ~uym., .§, 2 (1~30); Rev. Farm., 1.2, (too 74TTum. 10, 1 ( 932 • 10. -iedfeld, H. A., nAlc loi e~ de Trichocereus candi~!!Il....§. ' , ~esis del profes ra , ~o ario 931. 11. ·anchez, Dr. G. C., evist~ e Far!na c gi z. Medicina ~xperimen~al , i ma , Peru. , 1 48, 1· 1 , Vo1 • . o . 2, p. 143 12. Trier, G., Uber einfacne Pflanzenbasen etc., .berlin, 1912. 13. (1934.) chopf, C. and Beyerle, H., Ann., ill, 90 65 14. stockings, J., Journal of ·:1ental . ciences, 86, 29, 1940. 15. Organic ·ynt_heses, John viley and on Pub i her, ~ew fork, Collected Volume I, p. 522. 16. Orga~ic Syntheses, John ~iley nd on Pub ish r, New York, 17. Qrganic ynt_eses, John iiley an New ~ ork, on Pu i er, 18. Organic __ _ John 1 iley and Son Pu isher, New York, 19. onn, A., an chellenberg, • er. 50 . 1 513, 1917. 20. D 1 Amour • and _ rank r , . , - harm. fa Ro ork in Phxsi - C go, Ill 4 • 21. tehl , • J.J • n 11 wort and her. 0 - • 59, 114, 937. PU !CATI eringer, . , , niversit , .c •, J 0 ERAL I T in 1 7 • ·c 0 - ug enheim, ., Les amin s bio ogiques, ari 1934. ob chette A., Lud ena, F.P., m dicin les , ri 19 9. de • ouhier, A., ______ __ ui ait zeux emervei • • le Pey tl, aris 1 27.
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Olivier, Maurice
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Studies on cactus alkaloids and related synthesic [i.e. Synthetic] compounds
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School of Medicine
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Doctor of Philosophy
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Pharmacology
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1949-06
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06/01/1949
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06/01/1949
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