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SSR181507, a dopamine D(2) receptor antagonist and 5-HT(1A) receptor agonist. I: Neurochemical and electrophysiological profile.

Abstract
SSR181507 ((3-exo)-8-benzoyl-N-[[(2S)7-chloro-2,3-dihydro-1,4-benzodioxin-1-yl]methyl]-8-azabicyclo[3.2.1]octane-3-methanamine monohydrochloride) is a novel tropanemethanamine benzodioxane derivative that possesses high and selective affinities for D2-like and 5-HT(1A) receptors (K(I)=0.8, 0.2, and 0.2 nM for human D(2), D(3), and 5-HT(1A), respectively). In vivo, SSR181507 inhibited [(3)H]raclopride binding to D(2) receptors in the rat (ID(50)=0.9 and 1 mg/kg, i.p. in limbic system and striatum, respectively). It displayed D(2) antagonist and 5-HT(1A) agonist properties in the same concentration range in vitro (IC(50)=5.3 nM and EC(50)=2.3 nM, respectively, in the GTPgammaS model) and in the same dose range in vivo (ED(50)=1.6 and 0.7 mg/kg, i.p. on striatal DA and 5-HT synthesis, respectively, and 0.03-0.3 mg/kg, i.v. on dorsal raphe nucleus firing rate). It selectively enhanced Fos immunoreactivity in mesocorticolimbic areas as compared to the striatum. This regional selectivity was confirmed in electrophysiological studies where SSR181507, given acutely (0.1-3 mg/kg, i.p.) or chronically (3 mg/kg, i.p., o.d., 22 days), increased or decreased, respectively, the number of spontaneous active DA cells in the ventral tegmental area, but not in the substantia nigra. Moreover, SSR181507 increased both basal and phasic DA efflux (as assessed by microdialysis and electrochemistry) in the medial prefrontal cortex and nucleus accumbens, but not in the striatum. This study shows that the combination of D(2) receptor antagonism and 5-HT(1A) agonism, in the same dose range, confers on SSR181507 a unique neurochemical and electrophysiological profile and suggests the potential of this compound for the treatment of the main dimensions of schizophrenia.
AuthorsYves Claustre, Danielle De Peretti, Philippe Brun, Christiane Gueudet, Nathalie Allouard, Richard Alonso, Joëlle Lourdelet, André Oblin, Gabrielle Damoiseau, Dominique Françon, Marie-Françoise Suaud-Chagny, Régis Steinberg, Mireille Sevrin, Hans Schoemaker, Pascal George, Philippe Soubrié, Bernard Scatton
JournalNeuropsychopharmacology : official publication of the American College of Neuropsychopharmacology (Neuropsychopharmacology) Vol. 28 Issue 12 Pg. 2064-76 (Dec 2003) ISSN: 0893-133X [Print] England
PMID12902994 (Publication Type: Comparative Study, Journal Article)
Chemical References
  • (3-exo)-8-benzoyl-N-(((2S)7-chloro-2,3-dihydro-1,4-benzodioxin-1-yl)methyl)-8-azabicyclo(3.2.1)octane-3-methanamine monohydrochloride
  • Antipsychotic Agents
  • Dioxanes
  • Dopamine Antagonists
  • Dopamine D2 Receptor Antagonists
  • Piperazines
  • Proto-Oncogene Proteins c-fos
  • Pyridines
  • Receptors, Dopamine D2
  • Serotonin 5-HT1 Receptor Antagonists
  • Serotonin Antagonists
  • Sulfur Isotopes
  • Tropanes
  • Receptor, Serotonin, 5-HT1A
  • Guanosine 5'-O-(3-Thiotriphosphate)
  • Levodopa
  • N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide
  • 5-Hydroxytryptophan
  • Haloperidol
  • Dopamine
Topics
  • 5-Hydroxytryptophan (metabolism)
  • Action Potentials (drug effects)
  • Animals
  • Antipsychotic Agents (pharmacology)
  • Behavior, Animal (drug effects)
  • Binding Sites
  • Brain (anatomy & histology, drug effects, physiology)
  • Cell Count
  • Dioxanes (pharmacology)
  • Dopamine (metabolism)
  • Dopamine Antagonists (pharmacology)
  • Dopamine D2 Receptor Antagonists
  • Dose-Response Relationship, Drug
  • Drug Administration Schedule
  • Drug Interactions
  • Electric Stimulation
  • Electrochemistry (methods)
  • Guanosine 5'-O-(3-Thiotriphosphate) (pharmacokinetics)
  • Haloperidol (pharmacology)
  • Humans
  • Immunohistochemistry (methods)
  • In Vitro Techniques
  • Levodopa (metabolism)
  • Male
  • Microdialysis (methods)
  • Neurons (drug effects)
  • Piperazines (pharmacology)
  • Proto-Oncogene Proteins c-fos (metabolism)
  • Pyridines (pharmacology)
  • Radioligand Assay
  • Rats
  • Rats, Sprague-Dawley
  • Receptor, Serotonin, 5-HT1A (chemistry)
  • Receptors, Dopamine D2 (chemistry)
  • Serotonin 5-HT1 Receptor Antagonists
  • Serotonin Antagonists (pharmacology)
  • Sulfur Isotopes (pharmacokinetics)
  • Time Factors
  • Tropanes (pharmacology)

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