Thomas David R, Hagan Jim J
Department of Biology, Psychiatry Centre of Excellence for Drug Discovery, GlaxoSmithKline, Harlow, Essex, UK.
Curr Drug Targets CNS Neurol Disord. 2004 Feb;3(1):81-90. doi: 10.2174/1568007043482633.
Following the cloning of the 5-HT(7) receptor in 1993, studies to investigate 5-HT(7) receptor function in native tissues focused on identifying functional correlates that matched the pharmacological profile determined for the cloned receptor. Studies in peripheral tissues established that the 5-HT(7) receptor mediates the relaxation of smooth muscle, including the gastrointestinal tract and cardiovascular systems. Although a number of studies provided preliminary evidence for a role for the 5-HT(7) receptor in the circadian pacemaker function of the suprachiasmatic nucleus (SCN), additional studies to investigate 5-HT(7) receptor function in other brain regions have, until recently, been hindered by the absence of 5-HT(7) receptor-selective ligands. More recently, a number of 5-HT(7) receptor-selective antagonists including, SB-269970-A and SB-656104-A have been developed. Studies utilising these compounds suggest that the 5-HT(7) receptor modulates neuronal function in a number of brain areas including the hippocampus and thalamus. In turn, these findings suggest that 5-HT(7) receptor-selective ligands might prove therapeutically useful for the treatment of psychiatric disorders. In this respect there is increasing evidence to suggest that the 5-HT(7) receptor plays a role in the control of both circadian rhythms and sleep and might therefore represent a therapeutic target for the treatment of those disorders in which disturbances in circadian rhythms and sleep architecture are thought to be contributory factors. Furthermore, there is evidence to suggest that the receptor may play a role in other CNS disorders including, anxiety, cognitive disturbances and also migraine probably via both peripheral and central mechanisms. Although further studies are required to confirm the potential role of the receptor in such disorders, findings to date suggest there are exciting opportunities for the development of novel therapeutic agents acting either selectively at the 5-HT(7) receptor or whose profile of action includes an interaction with this receptor.
1993年5-HT(7)受体被克隆后，针对天然组织中5-HT(7)受体功能的研究集中于确定与克隆受体药理学特征相匹配的功能关联。外周组织研究表明，5-HT(7)受体介导包括胃肠道和心血管系统在内的平滑肌舒张。尽管多项研究为5-HT(7)受体在视交叉上核（SCN）的昼夜节律起搏器功能中发挥作用提供了初步证据，但直到最近，由于缺乏5-HT(7)受体选择性配体，对其他脑区5-HT(7)受体功能的进一步研究仍受到阻碍。最近，已经开发出多种5-HT(7)受体选择性拮抗剂，包括SB-269970-A和SB-656104-A。利用这些化合物的研究表明，5-HT(7)受体调节包括海马体和丘脑在内的多个脑区的神经元功能。反过来，这些发现表明5-HT(7)受体选择性配体可能在治疗精神疾病方面具有治疗作用。在这方面，越来越多的证据表明，5-HT(7)受体在昼夜节律和睡眠的控制中发挥作用，因此可能是治疗那些昼夜节律和睡眠结构紊乱被认为是促成因素的疾病的治疗靶点。此外，有证据表明该受体可能在包括焦虑、认知障碍以及偏头痛等其他中枢神经系统疾病中发挥作用，可能通过外周和中枢机制。尽管需要进一步研究来证实该受体在这些疾病中的潜在作用，但迄今为止的研究结果表明，开发选择性作用于5-HT(7)受体或其作用谱包括与该受体相互作用的新型治疗药物存在令人兴奋的机会。
