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 acetylcholin e storage, we have synthesized a series of semirigid vesamicol recepto r ligands based on the structure of 2-(4-phenylpiperidino)-cyclohexano l (vesamicol, AH5183, 1). In these compounds, the planes of the phenyl and piperidyl moieties of the parent ligand 1 are held at right angle s by vinyl, ethylene, and propylene bridges to form N-substituted deri vatives of spiro[indene-1,4'-piperidine], 2,3-dihydrospiro[indene-1,4' -piperidine], and 3,4-dihydrospiro[naphthalene-1(2H),4'-piperidine], r espectively. Preliminary evaluation of these compounds in electric org an synaptic vesicles revealed several potent vesamicol receptor ligand s, such as ahydronaphth-3-yl)spiro[1H-indene-1,4'-piperidine] (11b) an d phth-3-yl)spiro[2-bromo-1H-indene-1,4'-piperidine] (14), which displ ay subnanomolar affinity for this receptor. In general, the vinyl and ethylene bridges yielded the most potent analogs while the propylene-b ridged analogs were among the least potent compounds. The increased ri gidity of these spiro-fused compounds, relative to the corresponding s imple 4-phenylpiperidine derivatives of vesamicol, is expected to conf er greater selectivity for the vesamicol receptor.