S33138 [N-[4-[2-[(3aS,9bR)-8-cyano-1,3a,4,9b-tetrahydro[1]-benzopyrano[3,4-c]pyrrol-2(3H)-yl)-ethyl]phenylacetamide], a preferential dopamine D3 versus D2 receptor antagonist and potential antipsychotic agent: I. Receptor-binding profile and functional actions at G-protein-coupled receptors.
The novel, potential antipsychotic, S33138 (N-[4-[2-[(3aS,9bR)-8-cyano-1,3a,4,9b-tetrahydro[1]benzopyrano[3,4-c]pyrrol-2(3H)-yl)-ethyl]phenylacetamide), displayed approximately 25-fold higher affinity at human (h) dopamine D(3) versus hD(2L) (long isoform) and hD(2S) (short isoform) receptors (pK(i) values, 8.7, 7.1, and 7.3, respectively). Conversely, haloperidol, clozapine, olanzapine, and risperidone displayed similar affinities for hD(3), hD(2L), and hD(2S) sites. In guanosine-5'-O-(3-[(35)S]thio)-triphosphate ([(35)S]-GTPgammaS) filtration assays, S33138 showed potent, pure, and competitive antagonist properties at hD(3) receptors, displaying pK(B) and pA(2) values of 8.9 and 8.7, respectively. Higher concentrations were required to block hD(2L) and hD(2S) receptors. Preferential antagonist properties of S33138 at hD(3) versus hD(2L) receptors were underpinned in antibody capture/scintillation proximity assays (SPAs) of Galpha(i3) recruitment and in measures of extracellular-regulated kinase phosphorylation. In addition, in cells cotransfected with hD(3) and hD(2L) receptors that assemble into heterodimers, S33138 blocked (pK(B), 8.5) the inhibitory influence of quinpirole upon forskolin-stimulated cAMP formation. S33138 had low affinity for hD(4) receptors (<5.0) but revealed weak antagonist activity at hD(1) receptors (Galphas/SPA, pK(B), 6.3) and hD(5) sites (adenylyl cyclase, 6.5). Modest antagonist properties were also seen at human serotonin (5-HT)(2A) receptors (Galpha(q)/SPA, pK(B), 6.8, and inositol formation, 6.9) and at 5-HT(7) receptors (adenylyl cyclase, pK(B), 7.1). In addition, S33138 antagonized halpha(2C) adrenoceptors ([(35)S]GTPgammaS, 7.2; Galpha(i3)/SPA, 6.9; Galpha(o)/SPA, 7.3, and extracellular-regulated-kinase, 7.1) but not halpha(2A) or halpha(2B) adrenoceptors (<5.0). Finally, in contrast to haloperidol, clozapine, olanzapine, and risperidone, S33138 displayed negligible affinities for multiple subtypes of alpha(1)-adrenoceptor, muscarinic, and histamine receptor. In conclusion, S33138 possesses a distinctive receptor-binding profile and behaves, in contrast to clinically available antipsychotics, as a preferential antagonist at hD(3) versus hD(2) receptors.
Millan
Mark J
MJ
Institut de Recherches Servier, Centre de Recherches de Croissy, Psychopharmacology Department, 125 Chemin de Ronde, 78290 Croissy-sur-Seine, France. mark.millan@fr.netgrs.com
Mannoury la Cour
Clotilde
C
Novi
Francesca
F
Maggio
Roberto
R
Audinot
Valérie
V
Newman-Tancredi
Adrian
A
Cussac
Didier
D
Pasteau
Valérie
V
Boutin
Jean-A
JA
Dubuffet
Thierry
T
Lavielle
Gilbert
G
D000083:Acetanilides / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D014150:Antipsychotic Agents / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D001578:Benzopyrans / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D016466:CHO Cells; D019556:COS Cells; D002522:Chlorocebus aethiops; D006224:Cricetinae; D003412:Cricetulus; D018492:Dopamine Antagonists / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D065127:Dopamine D2 Receptor Antagonists; D004305:Dose-Response Relationship, Drug; D011485:Protein Binding / Q000187:drug effects / Q000502:physiology; D017448:Receptors, Dopamine D2 / Q000378:metabolism*; D050637:Receptors, Dopamine D3 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*
D000083:Acetanilides; D014150:Antipsychotic Agents; D001578:Benzopyrans; D018492:Dopamine Antagonists; D065127:Dopamine D2 Receptor Antagonists; C526614:N-(4-(2-(8-cyano-1,3a,4,9b-tetrahydro(1)benzopyrano(3,4-c)pyrrol-2(3H)-yl)ethyl)phenyl)acetamide; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3; D043562:Receptors, G-Protein-Coupled