(+/-)-2-Depentylperhydrohistrionicotoxin: A New Probe for a Regulatory Site on the Nicotinic Acetylcholine Receptor-Channel

Article abstract of DOI:10.1021/jm00350a007

(+/-)-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, an the quaternary methiodides 19 and 20 blocked the indirectly elicited twich.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 twich.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 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.