Slow dissociation of partial agonists from the D2 receptor is linked to reduced prolactin release

• Published in: The international journal of neuropsychopharmacology 2012-06, Vol.15 (5), p.645-656
• Main Authors: Carboni, Lucia, Negri, Michele, Michielin, Francesca, Bertani, Simone, Fratte, Sonia Delle, Oliosi, Beatrice, Cavanni, Paolo
• Format: Article
• Language: English
• Subjects: Animals; Antagonists; Antipsychotic Agents - pharmacology; Aripiprazole; Blood; Clozapine; Clozapine - pharmacology; Dibenzothiazepines - pharmacology; Dopamine Agonists - pharmacology; Dopamine Antagonists - pharmacology; Dopamine D2 Receptor Antagonists; Dopamine D2 receptors; Haloperidol; Haloperidol - pharmacology; Kinetics; Male; Motor task performance; Neuroleptics; Piperazines - pharmacology; Prolactin; Prolactin - antagonists & inhibitors; Prolactin - blood; Prolactin - secretion; quetiapine; Quetiapine Fumarate; Quinolones - pharmacology; Rats; Rats, Sprague-Dawley; Receptor mechanisms; Receptors, Dopamine D2 - agonists; Receptors, Dopamine D2 - metabolism
• ISSN: 1461-1457; 1469-5111
• DOI: 10.1017/S1461145711000824

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.