SELEX OCHULISH DERIVATIVES
llarch. 1961
229
Analogs of Parasympathetic Neuroeffectors. I. Acetylselenocholine, Selenocholine, and Related Compounds’ WOLFGANG H. H.
GUNTHER
AND
HENRY G. MATJTNER
Department of Pharmacology, Yale Cniversity School of Medicine, S e w Haven, Connecticut Recezted September 18, 1963 Acetylselenocholine, benzoylselenocholine, butyrylvelenocholine, selenocholine diselenide, and some of their dimethvl and monomethvl analogs have been prepared. The use of the Bunte salts of selenocysteamines for the - preparation of diselenidei is described.
L4cetylcholine is one of the rather small number of compounds the biological actions of which can be considered in terms of molecular interactions.* On the other hand, the pharma~ology3.~ of its sulfur analog, acetylthiocholine, a compound widely used as a histological ~ t a i nremains ,~ rather confusing. Recent work has indicated that in thioacyl and selenoacyl analogs, which are essentially isosteric, electron distribution and electron mobility are rather different, an effect responsible for the observation that selenoacyl compounds undergo aminolysis much more readily than isologous thioacyl compounds6-8 and for the differences in the spectra of thioacyl and selenoacyl analogs. Since electron distribution would be expected to differ in acetylcholine, acetylthiocholine, and acetylselenocholine, while these compounds presumably have a rather similar ability to fit receptor sites, a systematic study of the comparative pharmacology of this group of analogs, and of their reactions with true acetylcholinesterase, pseudocholinesterase, and with nucleophilic reagents, was initiated in the hope that it would provide additional information about the receptor sites to which these compounds attach themselves. The selenium of 2-aminoethylselenium compounds can be introduced by the reaction of the corresponding 2-aminoethyl halides with potaseium selenocyanate” lo after protection of the amino group. It has now been found that 2-aminoet~hylselenolsand the corresponding diselenides can be synthesized most conveniently by may of the intermediate formation of 2-aminoethyl selenosulfates, the Bunte salts of 2-aminoethylselenolc. Potassium selenosulfate, obtained by dissolving finely powdered selenium in an aqueous solution of potassium sulfite,” reacted smoothly wit’h 2-amino- and 2-alkylaminoethyl halide hydrohalides, to yield the inner salts of 2-aminoethyl selenosulfates (I-IV, Table I). Hy(1) This work was supported, in part, b y grants from the National Science Foundation (G-19329) and U. S. Public Health Service (CA-3937). (2) D. Nachmansohn, “Chemical and Molecular Basis of Nerve Activity,” Acadeniic Press, New York. N. Y., 1959. (3) R. R . Kensliaa, P. F. Dreisbach, R f . Ziff, and D. Green, J . Am. Chem. Soc., 6 0 , 1765 (1938).
(4) U’. F. Alexander, J. B. Dillon, and C Jordan, Proc. SOC.Ezptl. B i d . .%fed., 38, 566 (1938). ( 5 ) G. 13. Iioelle and J. Y. Friedenwald, ibid., 7 0 , 617 (1940). (6) H. G. Mautner and W. H. H. Gunther, J . Am. Chem. Soc., 83, 3342 (1961). (7) H. G . hlautner. S. I€. Cliu, arid W. H. €1. Giinther, Abstracts, IUPAC Congress, London, England, July, 1Y63, 1.4-132. (8) 1%. G. Mautner, S. H. Chu, and TV. H. H. Giinther, J . -4m. Chem. Soe., 8 6 , 3458 (1963). (9) V. Coblentz, Ber.. 24, 2131 (1891). (10) W.H. H. Giinther and H. G. hfautner, J . Am. Chem. Soc., 82, 2762 (1960).
(11) H. Rheinboldt in Honben-Weyl, “hfethoden der Organischen Chemie,” Vol. IX, Georn Thieine Verlag, Stuttgart, 1955. p. 1089.
drolysis with N hydrochloric acid a t 50-60” of the selenosulfates yielded the corresponding diselenides. These were yellolv oils from which the crystalline hydrochlorides (Y-YII, Table I) could be prepared. Bis(2-trimethylammoniumethyl)diselenide (VIII) could not be obtained in pure form by this route, due to contamination with inorganic salts. Diselenides could be reduced to the corresponding eelenols by sodium borohydride in water or in organic solvents in the presence of methanol, as noted previously.’* In all cases it was found that slightly more than 2 molar equivalents of sodium borohydride discharged the yellow color of the diselenides, yielding the sodium salts of the selenols, which were used for further reaction without isolation. 2-Aminoethyl selenobenzoates (XI-XIII, Table I) xere formed in good yield by treatment of the reduction products with benzoyl chloride in the presence of sodium bicarbonate buffer6; n’-methyl-S,Se-dibenzoyl selenocysteamine (XII) crystallized from the reaction mixture ; and 2-dimethylaminoethyl selenobenzoate (XIII) was isolated as the hydrochloride. Treatment of the free base of XI11 with methyl iodide in an ether-acetone mixture gave benzoylselenocholine iodide (XVI) in excellent yield. Se-Benzoylselenocholine bromide (XVII) and Se-butyrylselenocholine iodide (XVIII) were prepared in a similar fashion. Acetylseleriocholine (XIY, XV) could not be prepared z~iathe SchottenBaumann acylation since the intermediate 2-dimethylaminoethyl selenoacetate appeared to be unstable under the reaction conditions. 2-Dimethylaminoethyl diselenide (T’II) was, therefore, reduced in methanol solution, a large excess of acetic anhydride was added, and the mixture was evaporated to dryness under reduced pressure. The oily residue was extracted with a mixture of acetone and ether, filtered, and permitted to react with methyl iodide to yield acetylselenocholine iodide (XIV) as colorless prisms. Acetylselenocholine bromide was prepared in an analogous fashion. Quaternization of VI1 yielded the diselenide form of selenocholine as its diiodide (VIII). Methylation of the borohydride reduction product of VI1 in an ether-acetone mixture gave 2-triniethylammoniumethyl methyl selenide iodide (X). An attempt to suppress the methylation of the selenol group by addition of glacial acetic acid, as in the analogous synthesis of thiocholine, resulted in the preferred methylation of the selenol group, giviiig 2-dimethylaminoethyl methyl selenide hydriodidc (IX) instead of the expected isomeric (12) B. Sjoberg and S. Herdevall, Acta Chem. Scand., 12, 1347 (19.58). (13) l3. Hansen, A. l3. Pharinacia, Ugpsala, Sweden, personal colninuni-
cation.
230
\I,.
I 11
111
I\ \
\I \ I1 \XI I.\ .\
XI 111 1111 AI\* \ 1.\\ I A \ I1 A \ 111
reduced selenoclioliiie iodide. That IX \\-as a tertiary amine rather than a quaterriary anmioriium salt was estahlished 11y the pK, of this conipouiid being S.7, a, value similar to the pK, 8.4 of T'II. The seleiiol form of seleriocholine has, so far, not' h : i i othairied iii p u ~ e foriit. Yarious attempts t'o i d u c c its diseleiiide 01' t,o Iiydiulyzc its acetyl 01' h i oyl esters under alkaliiic. coiiditioiis r e d t e d largely 11 a c1t:coniposed prodiict' witli eliniiimtioii of triniet,liylilniii~c. ilttempts to piwipitatc the seleiiol \\-it11 va~iousheavy metal salts yielded impure precipitates or resulted in removal of xctleiiiuiii froin tlic orgaiiic moiety :tiid piwipitatioii of tlw itioigaiiic inetal seleiiides. . \ i i itivestigatioii of the coriiparat'ive phamiacologieal actmiorisof acetylcliolinc, acet,yltliioclioliiie, a d acetylscleiioclioline has heen undertakeu. It was fourid that \vhile the liydrolysis pi*oduct,of acet~ylcholine,choline, is relatively inert, ill the guinea pig ileum and fi.og rectus I, 11, 111, 1r-f' ahdoniiiiis preparationb, t l i e liydrolysis products clioliiictliiol and cholincseleiiol eslribit~niuscariiiic activit'ies c s c t w h g tliosc of t'lic ttsters from ~vliicht'liey ai'e dcrived. 15 Thus, ~ v l iICi pliysost~igmine, an acet,ylclioliiiostwase inhibitor, \vi11 greatly eiihaiicc t lie iiiuscariiiic activity of' ucet~ylclioliiic hy pre\witiiig its destiuct8ioii, it, recluc (' :iotiviticks of t,lit: uiialogous tliiolcstrr a i d scleit pivvcwti i;g t'lir toi*niutioii of' tlit: inore activc. p i d u c t s . Osidatioii oi' ~~lioIin(tliio1 aiid clioliii ol to tlir disulfidc a i i d tlisclt~iiidc, respectively, iwluces iiiuscariiiio nctivit'y. h i \-it:\\- of' ttie pliarriiacologically iiiiport,ant differences t)etwc1cti "single armed" aiitl "c!oubled arrncd" onium ~onipouiids,it slioultl Le iiot,cd that simple oxidatioii of clioliiiet,liiol or choliiiesclciiol ix:pwseiits a cotiveiiieiit Suiiitwing rcfcrs t o cciriipou~idsin Table I iiictmliodof coiivert,irig "single a r ~ i ~ c dinto " "douh1c:d al'lll"'' c~onlpouncls. ltelati\-e potciicies of t,lw :d)o\-e coi~ipouiiclsi i i tJic Experimental frog iwt.us alidoniiiii5 prcparatioii arc' suiiiiiiarized 2-Aminoethyl Selenosulfates (1, 11,111, IV).---A stirred susprni t i 'l'aljle 11. I k p e i h e i i t a l &.tails \\,ill t,c piiblisIi(id sicln of 7.9 g. of finrly pc,\vtlmd seleniun~in t: solution of 16 p. of '1
c:lsc~\\.lieIY~.
( I I 1 I\. .\. S c o t t arid 11. I'1~:ii~u~wiiI. K x p t l . 'I'licrtip
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