The CheIllistry of Peyote Al.kaloids! GOVIND J. KAPADIA AND M. B. E. FAYEZ Department of Pharmacognosy and Natural Products, College of Pharmacy, Howard University, Washington, D.C. 20001 The fact that several publications, reporting new constituents and biogenetic pathways of peyote, have appeared since the publication of our latest review article (I)-and surely more to come-and the organization of this Symposium all testify that interest in peyote is still far from extinguished. In the lapse of only the past 18 months, fifteen additional constituents of peyote have been reported, bringing the total number of identified constituents of this resourceful cactus to 56 at the time of writing this article. The earliest chemical studies with peyote were made by Lewin (2) in 1888 who isolated the first crystalline constituent, namely the tetrahydroisoqui- noline alkaloid anhalonine (XXXVIII; for structures, cf. table 1). With the realization that the latter compound possessed no hallucinatory effects, vigorous research was continued to discover the active principle. The studies of Heffter (3-8) towards the end of the century resulted in the discovery of three additional tetrahydroisoquinolines, pellotine (XXXV), anhalonidine (XXX), and lophophorine (XLI) and the identification of mescaline (XVII), a il-phene- thylamine, as the hallucinogenic principle of the drug. In 1899, another alkaloid, anhalamine (XXI), was isolated by Kauder (9). Ernst Spath must be ac- credited for the structure elucidation and the synthesis of all these alkaloids, publishing his results in a series of reports from 1919 and extending the scope of his investigations to include alkaloids from other Cactaceae up to 1939 (10-28). Spath's contributions included the isolation of five further peyote constituents, namely anhalinine (XXV), anhalidine (XXVII) (22, 23), N-methylmescaline (XVIII)(26), N-acetylmescaline (XX) (27), and O-methylanhalonidine (XXXIII)(28). Revival of interest in peyote started in the early 1960's with a report on glc studies (29) of its constituents which revealed the complexity of the alka- loidal mixture and thus drew attention to the seemingly forgotten plant. This coincided with the constantly-growing interest in hallucinogenic drugs in general and with the almost-sudden flourish of activity in biogenetic study. All was much facilitated-and perhaps stimulated-by the availability of modern tech- niques such as g1c, mass spectrometry and use of isotope tracers. The out- come was an avalanche of publications which, for the cactaceae plants, were extended to several species other than peyote, Lophophora willierneii (Lemaire) Coulter. The results of studies on peyote showed that this small- sized cactus is by far the richest in alkaloidal contents of all members of the family. The total alkaloidal content has been estimated (30) to be 3.7% for dried "upper slices of mescal buttons" and 0.41% for fresh peyote heads. Table 2 lists the figures reported by various workers for the percentages of some alkaloids in the plant. A recent study (31), based on measurement of g1cpeak areas, re- vealed the percentages given in the same table for the separate components based on the alkaloidal fraction of greenhouse-grown peyote.Those alkaloids which are not listed in table 2 are reported (31) to exist in only trace amounts. Seasonal variations have also been observed (31), whereby the contents of N-demethylated compounds (e.g., XXI and XXX) were higher during late tPt-eserrted 24 April 1972 at the Symposium on Peyote, Houston, Texas. The Symposium was sponsored by the Section on Pharmacognosy and Natural Products of the Academy of Pharmaceutical Sciences and the Ameri- can Society of Pharmacognosy. 9 TABLE 1. Peyote constituents. MONO-OXYGENATEDPHENETHYLAMINES Substituents References Number and Name Formula mp, bp/mm ..- .----_.,--_ ...__ ..._--------------------_._------_._---------_ ... _--------- -_._--_ •.._---- --_.- 33, 34 I. Tyramine. C,HllON 161° H HH 33 N-Methyltyramine. C,H1:ION 127-128° H H CH3 II. 32-34 III. Hordenine. C,oH"ON 117-118° H CH" CH, 33,34, 135 IV. Candicine" .. CI1H"O,N 230-231° H CH" CH,; (As iodide) DlOXYGENATEDPHENETHYLAMINES Rl~ R;P :::----.. I NRJRI, R, R2 R3 Rt ---------- H HH H 37 V. Dopamine .. ... _ ...... _. CSHl102N 241° (As HCI) H H CH3 37 VI. Epinine. C,H'302N 188-189° H H R R 37 VII. 4·Rydroxy -3-methoxyphenethy lamine .. C,R.302N CR. N·Methyl-4- hydroxy -3-methoxyphene- VIII. 37 thylamine .. CJOR"o"N 154--155° CR, H H CR. (As HCI) N,N·Dimethyl-4-hydroxy-3- '< IX. 37 0 methoxyphenethylamine. CnH1702N 190-191° CH, H CH, CH3 (As HCI) r CH, H H 39 w X. 3,4·Dimethoxyphenethylamine. ClOH",O,N 188°/15 CH" 0'1 o-Z ;i1::.. :d TRIOXYGENATED PHENETHYLAMINES AND THEIR AMIDES 3 o 11 COQl :r: RiO .-, NR3R~ •....• \0 OR "--l 2 W Rl R, R~ R, ----"----------------"-------------------------_. XI. 3,4-Dihydroxy-S-methoxy- ~ phenethylamine ... C"H1"0,,N 207° HHHH 37 ;.. '"d XII. 3-Hydroxy-4,S-dimethoxy- )- phenethylamine 0 (3-Demethylmescaline) ......... C1oH16O"N 178-179° CH" H HH 41, 42 :;: (As HCl) )- XIII. N-Methyl-3-hydroxy-4,S- Z dimethoxyphenethylamine .. CnHI7O"N 151-5° CH" H H CH" 43 0 (As HCI) "1 )- XIV. N-N-Dimethyl-3-hydroxy-4,5- >< dirnethoxyphenethylamine ...... C"H"O"N 180-185° CH" H CH" CH" 43 t>l (As HCI) N XV. N-FormyI-3-hydroxy-4,S- ___ h dirnethoxyphenethylamine. CuH1,,0.,N CH" H H COH 44 '"d XVI. t>l N-AcetyI-3-hydroxy-4,5- >< dimethoxyphenethylamine .......... ' C12H170.,N 102--103° CH" H H COCR, 44 0>.,) Mescaline _.. 30-32° XVII. Cl1HI7O"N CH" CH" HH 34, 80, 107 t>l 180°/12 ;.. XVIII. N-Methylmescaline .. , ............. C12H,,03N 177.5-178° CH" CH" H CH" 26,34 t"' (As picrate) ;.~. XIX. N-Formylmescaline .. ., .. .... C.,H17O,N 68-69° CH" CH'l H COH 44 t"' XX. C H,,,O.,N N-Acetylmescaline. _............... 13 93-94° CH" CH" H COCR, 27,34,44 0a (JJ •....• •....• •.... tv TABLE l. Continued. _.,.,--"'- ..- . TETRAHYDROISOQUINOLINES AND THEIR AMIDES R10Q:) 0.. NR5 n;p OR3 H" R, R, R" R, R" ... ---- ._,_._ .._ ...... _-----_ .. -,".- _.,.- .._----------- - -----_. __ .._---_ .•._---- XXI. Anhalamine ...... ...... C"H",O"N 189-191° CH" CH" H HH 8, 9, 34 _.". __ 1) 12 HH COH 44 XXII. N·Formylanhalamine .. C H",O,N ____ I) CH" CH" XXIII. N- Acety lanhalamine. .. .. ..... C1"Hl70,N CH'l CH" HH COCH" 44 XXIV. Isoanhalamine ...... ..... CUHl"O"N 213-215° H CH" CH3 H H 123 (As HEr) CH" H H 22, 34 XXV. Anhalinine ... .............. Cl,HI7O"N _61__-63° I> CH" CH" XXVI. N.Formylanhalinine. ..... Cl:>,HI7O,N CH" CH" CHa H COH 44 Anhalidine ........... C12Hl7O"N 131-133° CH" CH" H H CH;l 23, 34 t"" XXVII. t"' XXVIII. Anhalotine (as iodide). ... - ... Cl"H,u03NI 219-220° CH" CH" H H (CH"h 135 0 XXIX, Isoanhalidine ......... .... Cl,H1703N 215-218° H CH" CH" H CH" 123 >< (As HCl) tI . H CH" H CH" H 5, 34 XXX. Anhalonidine ... C'2 I7O"N ___160-161I>° CH" > XXXI. N-Formylanhalonidine ......... .... Cl"HI70,N CH" CH" H CHa COH 44 XXXII. Isoanhalonidine ........ C12Hl7O"N 209-211 ° H CH" CH" CH" H 123 (As HEr) XXXIII. S-( + )-O-Methylanhalonidine .....,. , . C,,,Hl,O,,N 140°/0.05, CH" CH" CH" CHa H 28, 34 +20.7° (MeOH) _____ 1) XXXIV. N-Formyl-O-methylanhalonidine. Cl,Hl"O.lN CH" CH" CH" CHI COH 44 CH, CH3 XXXV. Pellotine ........ C13Hl"O"N 111-112° CH" H CH" 4, 9, 34 XXXVI. Peyotine (as iodide) . ... -' C14H"O,NI 185-186° CH, CHa H CH" (CH"h 135 XXXVII. Isopellotine. ......... ... , .. , .. , C1"H19O;lN 212-222° H CH" CH" CHa CH" 123 (As HCl) ---CH,- H 2, 5, 34, 139, XXXVIII. S-( - )-Anhalonine .. '" . Cj2Hl,O"N 85.5°,-56.3° CH" CH" (CHC]') 140 ':2" ____ h 0 Cl;[H",O.lN CH;[ -CH2- CH:l COH 44 XXXIX. N-Formylanhalonine ... " . ~ XL. N·Acetylanhalonine. Cl,H17O,N ----" CH" -CH,- CH, COCH" 44 -CH - CH3 w XLI. S-( - )-Lophophorine. ... .... C"lHI7O;[N -47° CH" 2 CH" 5,34 0- (CHCII) XLII. Lophotine (as iodide) . C14H,uO;lNI 240·-242° CH" -CH2- CH" (CH"h 135 z - 3 C,H, o XLIII. Peyophorine . ........... C14H, ,,03N 155-156° CH, --CH2 CH 133 (As picrate) ,.... ts: » CONJUGATES WITH KREBS ACIDS ~ o XLIV. Mescaline succinimide. :r: Cu,H190,N 125-126° 44 •... 3 \0 11 C0100 ......• W "","I OCH q 3 RI (Rl =R2=H) R2 ~ XLV. Mescaline malimide. ____ I, » C,r.H,,,OGN XLIV, Rl=OH, R,=H 44 'U XLVI. Mescaline citrimide. C17H"OsN I, XLIV, Rl = OH, R, = CH,COOH 147 » ...•0 _____ 11 » XLVII. Mescaline maleimide. C",H"O,N 44 » Z 1I3COQ? 0 cO "1 ~~3 N » H3 r 'f ><! t'1 t<I XLVIII. Mescaline isocitrimide lactone ... C,7Hll.O,N ----I, 147 C0 'U t'1 H3 ::-....'q) ><! 0~ ",00 t'1 =3 l~T » t"' 0 ~ 0 » t"' ...•0 XLIX. Peyogiutarn .. 0 .. ' C'4H17O"N 217-219° 44 UJ 113 ::-.... N cO 0 ""'OR % (R=H) •... W -, TABLE L Continued. ___ h 44 L. Mescalotam ... XLIX, R =CH, 152, 153 LI. Mescaloxylic acid. 187-189° (R=H) 152, 153 LII. Mescaloruvic acid. 235-236.5° LI, R=CH" 237-238° 144, 151 LIII. Peyoxylic acid. H3CO~ H3CO~NH L' t'" HO R COOH 0 ><: (R=H) 0 144, 151 ;; LIV. Peyoruvic acid .. 233-234° LIII, R=CH, PYRROLE DERIVATIVES 131-133.5° 155 LV. Peyonine . H3CO~ H3cO V Rl T.r'On I R2 OCH 3 (R, =H, R2=COOH) ___ b 147 LVI. Pcyoglunal . LV, R, =CHO, R2=CH20H '<0 ~ «The presence of candicine was suggested (33) on the basis of tic evidence but could not be substantiated in a later study (135).