title: 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.
authors.affiliation: Sanofi-Synthelabo Recherche, Discovery Research, Bagneux, France. Yves.Claustre@Sanofi-Synthelabo.com
authors.forename: Yves
authors.initials: Y
authors.lastname: Claustre
authors.forename: Danielle De
authors.initials: DD
authors.lastname: Peretti
authors.forename: Philippe
authors.initials: P
authors.lastname: Brun
authors.forename: Christiane
authors.initials: C
authors.lastname: Gueudet
authors.forename: Nathalie
authors.initials: N
authors.lastname: Allouard
authors.forename: Richard
authors.initials: R
authors.lastname: Alonso
authors.forename: Joëlle
authors.initials: J
authors.lastname: Lourdelet
authors.forename: André
authors.initials: A
authors.lastname: Oblin
authors.forename: Gabrielle
authors.initials: G
authors.lastname: Damoiseau
authors.forename: Dominique
authors.initials: D
authors.lastname: Françon
authors.forename: Marie-Françoise
authors.initials: MF
authors.lastname: Suaud-Chagny
authors.forename: Régis
authors.initials: R
authors.lastname: Steinberg
authors.forename: Mireille
authors.initials: M
authors.lastname: Sevrin
authors.forename: Hans
authors.initials: H
authors.lastname: Schoemaker
authors.forename: Pascal
authors.initials: P
authors.lastname: George
authors.forename: Philippe
authors.initials: P
authors.lastname: Soubrié
authors.forename: Bernard
authors.initials: B
authors.lastname: Scatton
mesh_terms: D006916:5-Hydroxytryptophan / Q000378:metabolism; D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects; D001665:Binding Sites; D001921:Brain / Q000033:anatomy & histology / Q000187:drug effects* / Q000502:physiology; D002452:Cell Count; D004146:Dioxanes / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism; D018492:Dopamine Antagonists / Q000494:pharmacology; D065127:Dopamine D2 Receptor Antagonists; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004347:Drug Interactions; D004558:Electric Stimulation; D004563:Electrochemistry / Q000379:methods; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000493:pharmacokinetics; D006220:Haloperidol / Q000494:pharmacology; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D066298:In Vitro Techniques; D007980:Levodopa / Q000378:metabolism; D008297:Male; D017551:Microdialysis / Q000379:methods; D009474:Neurons / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D044282:Receptor, Serotonin, 5-HT1A / Q000737:chemistry; D017448:Receptors, Dopamine D2 / Q000737:chemistry; D058829:Serotonin 5-HT1 Receptor Antagonists; D012702:Serotonin Antagonists / Q000494:pharmacology; D013460:Sulfur Isotopes / Q000493:pharmacokinetics; D013997:Time Factors; D014326:Tropanes / Q000494:pharmacology
chemical_list: C480819:(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; D014150:Antipsychotic Agents; D004146:Dioxanes; D018492:Dopamine Antagonists; D065127:Dopamine D2 Receptor Antagonists; D010879:Piperazines; D016760:Proto-Oncogene Proteins c-fos; D011725:Pyridines; D017448:Receptors, Dopamine D2; D058829:Serotonin 5-HT1 Receptor Antagonists; D012702:Serotonin Antagonists; D013460:Sulfur Isotopes; D014326:Tropanes; D044282:Receptor, Serotonin, 5-HT1A; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D007980:Levodopa; C090413:N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide; D006916:5-Hydroxytryptophan; D006220:Haloperidol; D004298:Dopamine