Effects of recent and reference antipsychotic agents at human dopamine D 2 and D 3 receptor signaling in Chinese hamster ovary cells

Abstract

Olanzapine and sertindole were less efficacious dopamine antagonists in intact cell assays, possibly due to avid uptake in cells. For sertindole, the weak hD2S receptor antagonism in intact cells corresponded to a weak in vivo central dopamine antagonism assessed in rats. However, for olanzapine, hD2S receptor binding affinity correlated better with its in vivo dopamine antagonist potency. Such discrepancies may be further explained by relative differences of the compounds in penetrating into the brain.

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 D3versus D2Receptor Antagonist and Potential Antipsychotic Agent: I. Receptor-Binding Profile and Functional Actions at G-Protein-Coupled Receptors

“…Activation of hD 3 receptors by DA led to enhanced [ 35 S]GTP␥S binding Vanhauwe et al, 2000), an effect potently and reversibly blocked by S33138, indicating competitive antagonist properties. Moreover, using an SPA procedure coupled to a highly selective antibody (Millan et al, 2004a;Neve et al, 2004), the activation of G␣ i3 by DA was also shown to be antagonized by S33138.…”

“…The higher affinity of S33138 for hD 3 versus hD 2L and hD 2S receptors distinguishes it from haloperidol, clozapine, olanzapine, risperidone, and other clinically available antipsychotics displaying similar affinities for hD 3 , hD 2L , and hD 2S sites (Table 2) (Millan et al, 2000a;Vanhauwe et al, 2000;Burstein et al, 2005). Furthermore, the marked D 3 versus D 2 receptor preference of S33138 likewise differentiates it from aripiprazole and bifeprunox, which behave as partial agonists at hD 3 and hD 2 receptors (Shapiro et al, 2003;Burstein et al, 2005;Novi et al, 2007;Urban et al, 2007b).…”

“…Nonetheless, like their D 3 counterparts, both hD 2S and hD 2L receptors (which are principally localized presynaptically and postsynaptically to dopaminergic pathways, respectively) couple via G o/i to AC and ERK 1/2. Across a broad range of measures, [ 35 S]GTP␥S binding to hD 2L and hD 2S receptors (Vanhauwe et al, 2000;Newman-Tancredi et al, 2002), as well as hD 2L receptor coupling to G␣ i3 (Millan et al, 2004a;Lane et al, 2007), AC (O'Hara et al, 1996;Hall and Strange, 1999), and ERK 1/2 (Beom et al, 2004;Neve et al, 2004), S33138 behaved as a pure antagonist at both hD 2L and hD 2S receptors with lower potency than at hD 3 receptors. Recent work on "agonist-directed" trafficking and "protean" agonism at hD 2L sites emphasizes that drug efficacy can vary as a function of the intracellular pathway (Neve et al, 2004;Lane et al, 2007;Urban et al, 2007a).…”

“…Nonetheless, no clinically employed antipsychotic differentiates D 2 from D 3 receptors (Vanhauwe et al, 2000;Dean and Scarr, 2004;Burstein et al, 2005;Joyce and Millan, 2005), so their respective importance remains uncertain. Interestingly, several arguments support current interest in D 3 receptors as a target for the potentially improved treatment of schizophrenia (Joyce and Millan, 2005;Boeckler and Gmeiner, 2006;Sokoloff et al, 2006).…”

Aripiprazole has Functionally Selective Actions at Dopamine D2 Receptor-Mediated Signaling Pathways

“…Vanhauwe et al (2000) had reported that these compounds should be considered as D 2 receptor antagonists based on their inhibition of AC, although melperone was not studied by them. We hypothesized that a study of their regulation of D 2L function might reveal functional characteristics that explained some of their behavioral atypicality.…”