title: Slow dissociation of partial agonists from the D₂ receptor is linked to reduced prolactin release.
abstract: In this study we investigated the correlation between affinity, efficacy, peripheral receptor occupancy, and kinetic properties of D₂ dopamine receptor ligands with time-course evaluations of prolactin release in rat blood. We profiled typical and atypical antipsychotic antagonists at D₂ receptors, the partial agonist aripiprazole, and four novel partial agonist compounds with different properties. Clozapine and quetiapine revealed lower prolactin release and fast dissociation kinetics, linking fast dissociation and prolactin-sparing properties. Surprisingly, haloperidol, a highly prolactin-releasing antagonist, shared intermediate dissociation properties. Factors other than kinetic properties may thus contribute to prolactin-releasing properties of antagonists. Partial agonists sharing similar efficacies and receptor occupancies differed markedly in their ability to induce hyperprolactinaemia. Aripiprazole moderately released prolactin even at high receptor occupancies, with slow dissociation from D₂ receptors. Other compounds displaying low affinities and fast dissociations released prolactin substantially, although less than haloperidol. The effect augmented after repeated administrations. Compounds with high affinities and slow dissociation rates stimulated moderate prolactin release at high receptor occupancies, reaching a ceiling effect at 50-60% occupancy. Moreover, the effect developed tolerance. In conclusion, we investigated the affinity and kinetic properties of D₂ partial agonists associated with their ability to induce prolactin release in blood. We propose that for D₂ partial agonists, at comparable intrinsic activities and peripheral occupancies, the prolactin-releasing properties are linked to their kinetic rate properties. Differently from D₂ antagonists, partial agonists display slow dissociation and high affinity associated with a low prolactin release profile.
authors: Neuroscience Centre of Excellence for Drug Discovery, GlaxoSmithKline Medicine Research Centre, Verona, Italy. lucia.e.carboni@alice.it
authors: Lucia
authors: L
authors: Carboni
authors: Michele
authors: M
authors: Negri
authors: Francesca
authors: F
authors: Michielin
authors: Simone
authors: S
authors: Bertani
authors: Sonia Delle
authors: SD
authors: Fratte
authors: Beatrice
authors: B
authors: Oliosi
authors: Paolo
authors: P
authors: Cavanni
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D000068180:Aripiprazole; D003024:Clozapine / Q000494:pharmacology; D003987:Dibenzothiazepines / Q000494:pharmacology; D018491:Dopamine Agonists / Q000494:pharmacology*; D018492:Dopamine Antagonists / Q000494:pharmacology*; D065127:Dopamine D2 Receptor Antagonists; D006220:Haloperidol / Q000494:pharmacology; D008297:Male; D010879:Piperazines / Q000494:pharmacology; D011388:Prolactin / Q000037:antagonists & inhibitors / Q000097:blood / Q000378:metabolism*; D000069348:Quetiapine Fumarate; D015363:Quinolones / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017448:Receptors, Dopamine D2 / Q000819:agonists / Q000378:metabolism*
chemical_list: D014150:Antipsychotic Agents; D003987:Dibenzothiazepines; D018491:Dopamine Agonists; D018492:Dopamine Antagonists; D065127:Dopamine D2 Receptor Antagonists; D010879:Piperazines; D015363:Quinolones; D017448:Receptors, Dopamine D2; D000069348:Quetiapine Fumarate; D000068180:Aripiprazole; D011388:Prolactin; D003024:Clozapine; D006220:Haloperidol