(.+-.)-2-Depentylperhydrohistrionicotoxin: a new probe for a regulatory site on the nicotinic acetylcholine receptor-channel

(+/-)-2-Depentylperhydrohistrionicotoxin (4), several of its analogues, and N- and O-substituted derivatives were prepared and tested for their effects on the neuromuscular transmission of the frog sartorius muscle. Compound 4, its N-methyl derivative 5, the O-acetyl derivative 9, and the quaternary...

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Bibliographic Details
Published in:Journal of medicinal chemistry 1982-08, Vol.25 (8), p.919-925
Main Authors: Takahashi, Kimio, Jacobson, Arthur E, Mak, Chin Pong, Witkop, Bernhard, Brossi, Arnold, Albuquerque, Edson X, Warnick, J. E, Maleque, M. A, Bavoso, A, Silverton, J. V
Format: Article
Language:English
Subjects:
Amphibian Venoms - chemical synthesis
Amphibian Venoms - pharmacology
Amphibian Venoms - toxicity
Analgesics - chemical synthesis
Animals
Chemical Phenomena
Chemistry
In Vitro Techniques
Ion Channels - drug effects
Muscle Contraction - drug effects
Muscle, Smooth - drug effects
Rana pipiens
Receptors, Cholinergic - drug effects
Receptors, Nicotinic - drug effects
X-Ray Diffraction
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Summary:(+/-)-2-Depentylperhydrohistrionicotoxin (4), several of its analogues, and N- and O-substituted derivatives were prepared and tested for their effects on the neuromuscular transmission of the frog sartorius muscle. Compound 4, its N-methyl derivative 5, the O-acetyl derivative 9, and the quaternary methiodides 19 and 20 blocked the indirectly elicited twitch. The oxidation of 4 and 5 to ketones 12 and 14 and their reduction to the epimeric alcohols 17 and 18 afforded materials with substantially reduced activity. N-Acetylation of 4 to 11 changed the course of the activity to a transient potentiation of muscle twitch. Both 4 and 5 were not very toxic to mice after subcutaneous administration. (+/-)-7-n-Butyl-1-azaspiro[5,5]undecan-8-one (12) epimerized readily at room temperature to afford the epimer 13, and preparation of the hydrochloride of its N-methylated derivative 14 was accompanied by a retro-Michael reaction, affording the 2-n-butyl-3-[4-(methylamino)butyl]cyclohexene-2-one (22). The strongly hydrogen-bonded alcohol 4 was analyzed as the hydrobromide by a single-crystal X-ray analysis, confirming its structure.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm00350a007