Two active structures for hemicholinium-like action

Blase, B.W.; Loomis, Ted A.; Collins, J.A.; Sommer, Harold Z.

doi:10.1016/0041-008x(74)90046-5

Cited by 2 publications

(3 citation statements)

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“…As discussed previously the -NCCOgrouping of acetylcholine (7) has been found to be in the gauche conformation both in the crystal11 and in solution12 while the -NCCSgrouping of acetylthiocholine (8a) is in the trans conformation.13-15 One finds similar conformational differences for choline (9)20 and thiocholine (10).21 These conformational differences should carry over to and AcHC-3 (3) and their acyloxy sulfur-substituted analogues 11 and 12. This appears to be the case in the thio-HC-3 (11) that was synthesized in the seco form and which resisted all attempts at cyclization.…”

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confidence: 86%

“…It has been shown in studies of acetylcholine (7) and several related esters that the -NCCOgrouping is in the gauche conformation both in the crystal11 and in solution. 12 Substitution of the acyloxy oxygen of acetylcholine with either S or Se, however, leads to the trans conformation for the -NCCBgrouping in the acetylcholine derivatives 8a and 8b (a, B = S; b, B = Se).13-15 Although the depolarizing abilities of 8a and 8b are greatly altered in various pharmacological preparations,16-18 the molecules' roles as substrates of acetylcholinesterase are not altered.19 Similar conformational differences exist for choline (9)20 and thiocholine (10).21 These conformational differences should also carry over to HC-3 (1) and AcHC-3 (3) and their acyloxy sulfur-substituted analogues. Thus, as a logical continuation of our interest in both the configurational and conformational structure-activity relationships of cholinergic compounds, an extensive investigation of thio-seco-hemicholinium-3 (11) and acetylthio-secohemicholinium-3 (12) annd their relationships to HC-3 (1) and AcHC-3 (3) was initiated.…”

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confidence: 99%

“…4a, R = O of activity as had previously been suggested by the work of DiAugustine and Haarstad.9 Recently an investigation of norphenyl-HC-3 (5) and a seco derivative of norphenyl-HC-3 ( 6) was reported which likewise indicates that cyclization is not a prerequisite to HC-3-like activity. 10 The mechanism of action of 4a-c was also found to vary to some extent with the type of substituent. It was interesting that AcHC-3 (3) was found to bind irreversibly to acetylcholinesterase or butyrylcholinesterase without deesterification in vitro in buffered aqueous solution at pH 7.4.…”

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confidence: 99%

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Effect of sulfur substitution for the noncarbonyl oxygen in hemicholinium-3 and acetyl-seco-hemicholinium-3. Synthesis, biological activity, and structure-toxicity relations. 2

Fr¹,

Dm²,

Hc³

et al. 1977

J. Med. Chem.

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As a continuation of our efforts to develop and study inhibitors which act presynaptically on neuromuscular function, sulfur analogues of hemicholinium-3 (HC-3, 1) and acetyl-seco-hemicholinium-3 (AcHC-3, 3) were prepared. In each case sulfur is substituted for the noncarbonyl oxygen in HC-3 (1) and AcHC-3 (3). As expected on the basis of conformational differences between acetylcholine and acetylthiocholine both of the thio analogues are produced in the seco form and do not cyclize spontaneously or when subjected to aqueous, acidic conditions up to 100 degrees C. Both compounds are stable in aqueous pH 7.4 solutions at 37 degrees C and in slightly acidic D2O solutions for more than 24 h. While thio-seco-hemicholinium 3 (11) is stable in the presence of acetylcholinesterase and butyrylcholinesterase in H2O at pH 7.4, acetylthio-seco-hemicholinium-3 (12) reacts within seconds to form the hemiacetal form of thiohemicholinium-3 (16). Mouse toxicity studies (LD50) indicate that while 12 is approximately as toxic as HC-3 (1) and AcHC-3 (3), 11 is 226 times less toxic. As in the studies with 1 and 3, mice were protected from 11 by choline and slightly by neostigmine. It is of interest, however, that almost equal and intermediate protection against 12 was afforded by choline and neostigmine. Structure-toxicity relationships of 1,3,11, 12, and 16 are discussed.

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confidence: 86%