Spirovesamicols: conformationally restricted analogs of 2-(4-phenylpiperidino)cyclohexanol (vesamicol, AH5183) as potential modulators of presynaptic cholinergic function.

In an effort to develop selective inhibitors of vesicular acetylcholine storage, we have synthesized a series of semirigid vesamicol receptor ligands based on the structure of 2-(4-phenylpiperidino)-cyclohexanol (vesamicol, AH5183, 1). In these compounds, the planes of the phenyl and piperidyl moieties of the parent ligand 1 are held at right angles by vinyl, ethylene, and propylene bridges to form N-substituted derivatives of spiro[indene-1,4'-piperidine], 2,3-dihydrospiro[indene-1,4'-piperidine], and 3,4-dihydrospiro[naphthalene-1(2H),4'-piperidine], respectively. Preliminary evaluation of these compounds in electric organ synaptic vesicles revealed several potent vesamicol receptor ligands, such as 1'-(2-hydroxy-1,2,3,4-tetrahydronaphth-3-yl)spiro[1H-indene-1,4'-p iperidine (11b) and 1'-(2-hydroxy-1,2,3,4-tetrahydronaphth-3-yl)spiro[2-bromo-1H-in den e- 1,4'-piperidine] (14), which display subnanomolar affinity for this receptor. In general, the vinyl and ethylene bridges yielded the most potent analogs while the propylene-bridged analogs were among the least potent compounds. The increased rigidity of these spiro-fused compounds, relative to the corresponding simple 4-phenylpiperidine derivatives of vesamicol, is expected to confer greater selectivity for the vesamicol receptor.