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.
Efange
S M
SM
Department of Radiology, University of Minnesota, Minneapolis 55455.
Khare
A B
AB
Foulon
C
C
Akella
S K
SK
Parsons
S M
SM
D000109:Acetylcholine / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000475:Alkenes / Q000737:chemistry; D000818:Animals; D004557:Electric Organ / Q000378:metabolism; D005030:Ethylenes / Q000737:chemistry; D007192:Indenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D008968:Molecular Conformation; D015394:Molecular Structure; D009467:Neuromuscular Depolarizing Agents; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry* / Q000378:metabolism; D011950:Receptors, Cholinergic / Q000378:metabolism; D013329:Structure-Activity Relationship; D013572:Synaptic Vesicles / Q000378:metabolism; D014753:Vinyl Compounds / Q000737:chemistry
C088808:1'-(2-hydroxy-1,2,3,4-tetrahydro-naphth-3-yl)spiro(2-bromo-1H-indene-1,4'-piperidine); D000475:Alkenes; D005030:Ethylenes; D007192:Indenes; D009467:Neuromuscular Depolarizing Agents; D010880:Piperidines; D011950:Receptors, Cholinergic; D014753:Vinyl Compounds; C083232:vesamicol receptor; C088807:1'-(2-hydroxy-1,2,3,4-tetrahydronaphth-3-yl)spiro(1H-indene-1,4'-piperidine); C006189:vesamicol; C036216:ethylene; C013658:propylene; D000109:Acetylcholine