The discovery and structure-activity relationships of 1,2,3,6-tetrahydro-4-phenyl-1-[(arylcyclohexenyl)alkyl]pyridines. Dopamine autoreceptor agonists and potential antipsychotic agents.
A novel dopamine (DA) autoreceptor agonist, 1,2,3,6-tetrahydro-4-phenyl-1- [(3-phenyl-3-cyclohexen-1-yl)methyl]pyridine (14), was identified. The structure-activity relationships surrounding this compound were studied by synthesis of analogues and evaluation of their dopaminergic activity. The cyclohexene substitution pattern was varied along with the length of the chain connecting the 1,2,3,6-tetrahydro-4-phenylpyridine to the cyclohexene. Compound 14, having the 1,3-substitution pattern and a single methylene chain, was the most potent. The 1,2,3,6-tetrahydro-4-phenylpyridine could be replaced by other aryl-cyclic amines with a slight loss in activity. The phenyl group on the cyclohexene ring could be para substituted; electron-donating groups were better tolerated than electron-withdrawing groups. Finally, the enantiomers of 14 were resolved via the 1,1'-binaphthyl-2,2'-diyl hydrogen phosphate salts. Although both isomers were partial DA agonists, the (+)-enantiomer had higher intrinsic activity than the (-)-enantiomer. Syntheses were developed that allowed rapid preparation of analogues. An X-ray crystal structure determination of an intermediate identified the (+)-isomer of 14 as having R configuration. This compound, designated CI-1007 (PD 143188), was found to have antipsychotic-like activity in behavioral tests; in particular, it was orally active in the conditioned avoidance test in squirrel monkeys with an ED50 of 0.6 mg/kg. The overall profile suggests that (R)-(+)-14 may be a clinically useful antipsychotic agent.
Wright
J L
JL
Department of Chemistry, Parke-Davis Pharmaceutical Research, Ann Arbor, Michigan 48105.
Caprathe
B W
BW
Downing
D M
DM
Glase
S A
SA
Heffner
T G
TG
Jaen
J C
JC
Johnson
S J
SJ
Kesten
S R
SR
MacKenzie
R G
RG
Meltzer
L T
LT
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000031:analogs & derivatives*; D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D014150:Antipsychotic Agents / Q000737:chemistry* / Q000494:pharmacology; D001362:Avoidance Learning / Q000187:drug effects; D001921:Brain / Q000378:metabolism; D016466:CHO Cells; D006224:Cricetinae; D018360:Crystallography, X-Ray; D000242:Cyclic AMP / Q000378:metabolism; D003510:Cyclohexanes / Q000737:chemistry; D053138:Cyclohexenes; D004298:Dopamine / Q000096:biosynthesis; D018491:Dopamine Agonists / Q000737:chemistry* / Q000494:pharmacology; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D009043:Motor Activity; D011725:Pyridines / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D011954:Receptors, Dopamine / Q000378:metabolism; D012453:Saimiri; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013378:Substantia Nigra / Q000502:physiology
D014150:Antipsychotic Agents; D003510:Cyclohexanes; D053138:Cyclohexenes; D018491:Dopamine Agonists; D011725:Pyridines; D011954:Receptors, Dopamine; C052568:cyclohexene; C090025:1,2,3,6-tetrahydro-4-phenyl-1-((3-phenyl-3-cyclohexen-1-yl)methyl)pyridine; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D000242:Cyclic AMP; D004298:Dopamine