Neuroscience Centre of Excellence for Drug Discovery, GlaxoSmithKline Medicine Research Centre, Verona, Italy.
Int J Neuropsychopharmacol. 2012 Jun;15(5):645-56. doi: 10.1017/S1461145711000824. Epub 2011 Jun 9.
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.
在这项研究中，我们调查了 D₂ 多巴胺受体配体的亲和力、效力、外周受体占有率和动力学特性与大鼠血液中催乳素释放的时程评估之间的相关性。我们对 D₂ 受体的典型和非典型抗精神病拮抗剂、部分激动剂阿立哌唑以及四种具有不同特性的新型部分激动化合物进行了剖析。氯氮平和喹硫平显示出较低的催乳素释放和快速解离动力学，这将快速解离和催乳素节约特性联系起来。令人惊讶的是，高度催乳素释放拮抗剂氟哌啶醇具有中间解离特性。因此，除了动力学特性之外，其他因素可能会影响拮抗剂的催乳素释放特性。具有相似效力和受体占有率的部分激动剂在诱导高催乳素血症的能力方面存在显著差异。阿立哌唑即使在高受体占有率下也能适度释放催乳素，并且与 D₂ 受体的解离速度较慢。其他显示低亲和力和快速解离的化合物虽然不及氟哌啶醇，但也会大量释放催乳素。这种效应在重复给药后会增强。具有高亲和力和缓慢解离率的化合物在高受体占有率下刺激适度的催乳素释放，在 50-60%占有率时达到上限效应。此外，这种效应产生了耐受性。总之，我们研究了与 D₂ 部分激动剂诱导血液中催乳素释放能力相关的亲和力和动力学特性。我们提出，对于具有相当内在活性和外周占有率的 D₂ 部分激动剂，催乳素释放特性与其动力学速率特性相关。与 D₂ 拮抗剂不同，部分激动剂显示出与低催乳素释放谱相关的缓慢解离和高亲和力。
