Substituted (S)-phenylpiperidines and rigid congeners as preferential dopamine autoreceptor antagonists: synthesis and structure-activity relationships.
A series of (S)-phenylpiperidines in which the substituents on the aromatic ring and nitrogen have been varied has been prepared. They have been evaluated pharmacologically to explore the importance of these substituents for the interaction with central dopamine (DA) receptors. On the basis of biochemical and behavioral data in rats, several of these compounds are characterized as centrally acting DA autoreceptor antagonists. (S)-Phenylpiperidines having an aromatic substituent with a high group dipole moment in the 3-position, i.e., meta with respect to the piperidine ring, and being N-substituted with a propyl group were found to be highly active in vivo on the synthesis and turnover of dopamine. However, they do not induce strong hypoactivity or catalepsy. Interestingly, the most active compounds in vivo were found to display only low affinity for DA D2 and D3 receptors in vitro. In addition, 7-triflate-substituted octahydrobenzo[f]quinolines and 6-triflate-substituted hexahydro-1H-benz[e]indoles have been prepared and pharmacologically evaluated. The trans isomers of these rigid structures were found to display a pharmacological profile similar to that of the flexible phenylpiperidines. The corresponding cis isomers were found to be inactive in vivo.
Sonesson
C
C
Department of Pharmacology, University of Göteborg, Sweden.
Lin
C H
CH
Hansson
L
L
Waters
N
N
Svensson
K
K
Carlsson
A
A
Smith
M W
MW
Wikström
H
H
D000818:Animals; D001552:Benzazepines / Q000378:metabolism; D001921:Brain / Q000378:metabolism; D016466:CHO Cells; D006224:Cricetinae; D004295:Dihydroxyphenylalanine / Q000378:metabolism; D065127:Dopamine D2 Receptor Antagonists; D006185:Habituation, Psychophysiologic; D007202:Indicators and Reagents; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D013058:Mass Spectrometry; D015394:Molecular Structure; D009043:Motor Activity / Q000187:drug effects*; D009904:Optical Rotation; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D017447:Receptors, Dopamine D1 / Q000037:antagonists & inhibitors*; D011985:Receptors, Serotonin / Q000502:physiology; D012110:Reserpine / Q000494:pharmacology; D012702:Serotonin Antagonists; D013134:Spiperone / Q000378:metabolism; D013329:Structure-Activity Relationship; D014162:Transfection
D001552:Benzazepines; D065127:Dopamine D2 Receptor Antagonists; D007202:Indicators and Reagents; D010880:Piperidines; D017447:Receptors, Dopamine D1; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D013134:Spiperone; D004295:Dihydroxyphenylalanine; D012110:Reserpine