Synthesis, in vitro acetylcholine-storage-blocking activities, and biological properties of derivatives and analogues of trans-2-(4-phenylpiperidino)cyclohexanol (vesamicol).
Eighty-four analogues and derivatives of the acetylcholine-storage-blocking drug trans-2-(4-phenylpiperidino)-cyclohexanol (vesamicol) were synthesized, and their potencies were evaluated with the acetylcholine active-transport assay utilizing purified synaptic vesicles from Torpedo electric organ. The parent drug exhibits enantioselectivity, with (-)-vesamicol being 25-fold more potent than (+)-vesamicol. The atomic structure and absolute configuration of (+)-vesamicol were determined by X-ray crystallography. The absolute configuration of (-)-vesamicol is 1R,2R. Structure-activity evidence indicates that (-)-vesamicol does not act as an acetylcholine analogue. Alterations to all three rings can have large effects on potency. Unexpectedly, analogues locking the alcohol and ammonium groups trans-diequatorial or trans-diaxial both exhibit good potency. A potent benzovesamicol family has been discovered that is suitable for facile elaboration of the sort useful in affinity labeling and affinity chromatography applications. A good correlation was found between potencies as assessed by the acetylcholine transport assay and LD50 values in mouse.
Rogers
G A
GA
Department of Chemistry, University of California, Santa Barbara 93106.
Parsons
S M
SM
Anderson
D C
DC
Nilsson
L M
LM
Bahr
B A
BA
Kornreich
W D
WD
Kaufman
R
R
Jacobs
R S
RS
Kirtman
B
B
D000109:Acetylcholine / Q000031:analogs & derivatives / Q000378:metabolism*; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D055598:Chemical Phenomena; D002621:Chemistry; D004557:Electric Organ / Q000378:metabolism; D007928:Lethal Dose 50; D051379:Mice; D015394:Molecular Structure; D009294:Narcotics; D009467:Neuromuscular Depolarizing Agents; D010622:Phencyclidine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology / Q000633:toxicity; D010880:Piperidines; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013572:Synaptic Vesicles / Q000378:metabolism; D014101:Torpedo; D014961:X-Ray Diffraction
D009294:Narcotics; D009467:Neuromuscular Depolarizing Agents; D010880:Piperidines; C006189:vesamicol; D010622:Phencyclidine; D000109:Acetylcholine