title: Towards a new generation of potential antipsychotic agents combining D2 and 5-HT1A receptor activities.
abstract: We report the discovery and the synthesis of novel, potential antipsychotic compounds combining potent dopamine D2 receptor antagonist and serotonin 5-HT1A receptor agonist properties in the same molecule. We describe the structure-activity relationship that lead us to the promising derivative: N-[(2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy)ethyl]-3-(cyclopent-1-enyl)-benzylamine 16. The latter has high affinity for D2 and 5-HT1A receptors, whereas it possesses only a weak affinity for 5-HT2A sites. In cellular models of signal transduction, 16 behaves as a silent antagonist at rD2 receptors while activating h5-HT1A receptors with an efficacy at least equivalent to that of the prototypical 5-HT1A agonist (+/-)-8-OH-DPAT. These dual actions confer a unique pharmacological profile to the product. In a behavioral model predictive of positive symptoms, 16 has an activity comparable to that of the typical antipsychotic haloperidol, while it is devoid of cataleptogenic effects. Although it produces behaviors characteristic of 5-HT1A receptor activation in rats, these occur at doses 100 times higher than those with (+/-)-8-OH-DPAT. We believe that the relative balance of D2 and 5-HT1A actions in 16 is appropriate, possibly optimal, to ensure superior efficacy and tolerability over existing antipychotic drugs.
authors.affiliation: Pierre Fabre Research Center, 17 avenue Jean Moulin, 81106 Castres Cedex, France.
authors.forename: Stephane
authors.initials: S
authors.lastname: Cuisiat
authors.forename: Nathalie
authors.initials: N
authors.lastname: Bourdiol
authors.forename: Vincent
authors.initials: V
authors.lastname: Lacharme
authors.forename: Adrian
authors.initials: A
authors.lastname: Newman-Tancredi
authors.forename: Francis
authors.initials: F
authors.lastname: Colpaert
authors.forename: Bernard
authors.initials: B
authors.lastname: Vacher
mesh_terms: D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000494:pharmacology; D000818:Animals; D014150:Antipsychotic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects; D001572:Benzofurans / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001596:Benzylamines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D065127:Dopamine D2 Receptor Antagonists; D006367:HeLa Cells; D006801:Humans; D011869:Radioligand Assay; D051381:Rats; D058825:Serotonin 5-HT1 Receptor Agonists; D015398:Signal Transduction; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D014150:Antipsychotic Agents; D001572:Benzofurans; D001596:Benzylamines; D065127:Dopamine D2 Receptor Antagonists; C518313:N-((2,2-dimethyl-2,3-dihydrobenzofuran-7-yloxy)ethyl)-3-(cyclopent-1-enyl)benzylamine; D058825:Serotonin 5-HT1 Receptor Agonists; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin