Penn State University College of Medicine - Milton S. Hershey Medical Center Department of Pharmacology. R130 500 University Dr., PO Box 850, Hershey, PA 17033-0850, USA.
Curr Pharm Des. 2010;16(5):488-501. doi: 10.2174/138161210790361461.
Functional selectivity is the term that describes drugs that cause markedly different signaling through a single receptor (e.g., full agonist at one pathway and antagonist at a second). It has been widely recognized recently that this phenomenon impacts the understanding of mechanism of action of some drugs, and has relevance to drug discovery. One of the clinical areas where this mechanism has particular importance is in the treatment of schizophrenia. Antipsychotic drugs have been grouped according to both pattern of clinical action and mechanism of action. The original antipsychotic drugs such as chlorpromazine and haloperidol have been called typical or first generation. They cause both antipsychotic actions and many side effects (extrapyramidal and endocrine) that are ascribed to their high affinity dopamine D(2) receptor antagonism. Drugs such as clozapine, olanzapine, risperidone and others were then developed that avoided the neurological side effects (atypical or second generation antipsychotics). These compounds are divided mechanistically into those that are high affinity D(2) and 5-HT(2A) antagonists, and those that also bind with modest affinity to D(2), 5-HT(2A), and many other neuroreceptors. There is one approved third generation drug, aripiprazole, whose actions have been ascribed alternately to either D(2) partial agonism or D(2) functional selectivity. Although partial agonism has been the more widely accepted mechanism, the available data are inconsistent with this mechanism. Conversely, the D(2) functional selectivity hypothesis can accommodate all current data for aripiprazole, and also impacts on discovery compounds that are not pure D(2) antagonists.
功能性选择性是一个术语，用于描述能够通过单一受体引起显著不同信号转导的药物（例如，在一种途径中为完全激动剂，而在另一种途径中为拮抗剂）。最近人们广泛认识到，这种现象影响了对某些药物作用机制的理解，并与药物发现有关。在临床领域，这种机制尤其重要的一个方面是治疗精神分裂症。抗精神病药物根据临床作用模式和作用机制进行分类。氯丙嗪和氟哌啶醇等最初的抗精神病药物被称为典型或第一代药物。它们既能产生抗精神病作用，又能产生许多副作用（锥体外系和内分泌），这些副作用归因于它们对多巴胺 D2 受体的高亲和力拮抗作用。然后开发了氯氮平、奥氮平、利培酮等药物，它们避免了神经副作用（非典型或第二代抗精神病药）。这些化合物在机制上分为高亲和力 D2 和 5-HT2A 拮抗剂，以及那些对 D2、5-HT2A 和许多其他神经受体具有适度亲和力的化合物。目前有一种获批的第三代药物阿立哌唑，其作用被归因于 D2 部分激动或 D2 功能选择性。尽管部分激动已被更广泛接受为作用机制，但现有数据与该机制不一致。相反，D2 功能选择性假说可以解释阿立哌唑的所有现有数据，并且还影响到不是纯 D2 拮抗剂的发现化合物。
