Effects off pyrroloisoquinoline enantiomers ((+)- and (-)-McN-5652-Z) on behavioral and pharmacological serotonergic mechanisms in rats

Donald F. Smith, Peer N. Jensen, Steen H. Poulsen, Erich O. Mikkelsen, Elizabeth Elbaz, Robert Glaser

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13 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)85-92
Number of pages8
JournalEuropean Journal of Pharmacology
Volume196
Issue number1
DOIs
StatePublished - 10 Apr 1991

Keywords

  • (Conformation)
  • (Molecular mechanics)
  • (Stereochemistry)
  • 5-HT (5-hydroxytryptamine, serotonin)
  • 5-HT uptake
  • Antidepressants
  • Hypermotility
  • Hyperthermia
  • MAO
  • Monoamine oxidase
  • Paroxetine binding
  • Vasocontraction

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