Effects of pyrroloisoquinoline enantiomers ((+)- and (-)-McN-5652-Z) on behavioral and pharmacological serotonergic mechanisms in rats.
A behavioral syndrome consisting of 5-hydroxytryptamine (5-HT)-dependent behaviors (e.g. forepaw treading, retropulsion and splayed hindlimbs) as well as hyperthermia occurred after bilateral injection of the (6S, 10bR)-(+)-enantiomer of McN-5652-Z into the cerebral ventricles in pargyline-treated rats. Both the behavioral syndrome and hyperthermia produced by (+)-McN-5652-Z were counteracted by parachlorophenylalanine or ketanserin. The (6R, 10bS)-(-)-enantiomer of McN-5652-Z influenced neither behavior nor body temperature. The enantiomers of McN-5652-Z differed also in their ability to inhibit ex vivo binding of paroxetine in rat frontal cortex and hypothalamus, in vitro uptake of 5-HT in rat blood platelets, and 5-HT-induced contraction of rat vascular smooth muscle, with (+)-McN-5652-Z being most active. No difference was observed between the effects of (+)- and (-)-McN-5652-Z on 5-HT metabolism by rat brain monoamine oxidase. Molecular models of N-protonated enantiomers having a cis B,C-ring juncture and a B-ring chair conformation were differentiated using a hypothetical model of the 5-HT uptake area. The findings indicate that the enantiomers of McN-5652-Z are useful tools for studying the stereoselectivity of behavioral and pharmacological effects exerted by serotonergic neurotransmission.
Smith
D F
DF
Psychopharmacology Research Unit, Psychiatric Hospital, Risskov, Denmark.
Jensen
P N
PN
Poulsen
S H
SH
Mikkelsen
E O
EO
Elbaz
E
E
Glaser
R
R
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D001831:Body Temperature / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D007546:Isoquinolines / Q000494:pharmacology*; D008297:Male; D008995:Monoamine Oxidase / Q000187:drug effects / Q000378:metabolism; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D017374:Paroxetine; D010880:Piperidines / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D012701:Serotonin / Q000378:metabolism / Q000494:pharmacology* / Q000502:physiology; D012702:Serotonin Antagonists / Q000378:metabolism / Q000494:pharmacology*; D013237:Stereoisomerism
D007546:Isoquinolines; D010880:Piperidines; D012702:Serotonin Antagonists; D012701:Serotonin; D017374:Paroxetine; C058079:McN 5652; D008995:Monoamine Oxidase