Send Orders of Reprints at bspsaif@emirates.net.ae Current Medicinal Chemistry, 2013, 20, 371-377 371 Serotonin Receptors of Type 6 (5-HT6): From Neuroscience to Clinical Pharmacology Donatella Marazziti 1,* , Stefano Baroni 1 , Franco Borsini 2 , Michela Picchetti 1 , Elena Vatteroni 1 , Valentina Falaschi 1 and Mario Catena-Dell’Osso 1 1 Dipartimento di Psichiatria, Neurobiologia, Farmacologia e Biotecnologie, University of Pisa; 2 Sigma-Tau “Industrie Farmaceu- tiche Riunite”, Roma, Italy Abstract: The serotonin (5-HT) receptors of type 6 (5-HT6) are quite different from all other 5-HT receptors, as they include a short third cytoplasmatic loop and a long C-terminal tail, and one intron located in the middle of the third cytoplasmatic loop. A lot of controversies still exist regarding their binding affinity, effects of 5-HT6 ligands on brain catecholamines, behavioral syndromes regulated by them, and brain distribution. In spite of the lack of information on metabolic pattern of the various compounds, some of 5-HT6 receptor ligands entered the clinical development as potential anti-dementia, antipsychotic, antidepressant and anti-obese drugs. The present paper is a comprehensive review on the state of art of the 5-HT6 receptors, while highlighting the potential clinical applica- tions of 5-HT6 receptor agonists/antagonists. Keywords: Serotonin, serotonin receptors, serotonin receptors of type 6, agonists, antagonists, neurochemistry, distribution, clinical pharma- cology INTRODUCTION Serotonin (5-HT) is a neurotransmitter widely distributed in the central nervous system (CNS) and in periphery involved in the regulation of several physiological functions, such as appetite, memory, sleep, learning, sexuality impulsivity, mood and anxiety. Not surprisingly, it is also considered to play a relevant role in the pathophysiology of different psychiatric conditions, in particular depression, anxiety, obsessive-compulsive and eating disorders, as well as schizophrenia [1, 2]. Seven families of 5-HT (5-HT1 / 5-HT7) receptors have been identified up to-now, including a total of 14 different receptor sub- types [3]. The 5-HT receptors of type 6 (5-HT6), the latest 5-HT receptors identified, are different from all other 5-HT receptors. Indeed, they are formed by a short third cytoplasmatic loop and a long C-terminal tail, and include one intron situated in the middle of the third cytoplasmatic loop. The observation that some antide- pressants and antipsychotics behaved as antagonists at their level greatly attracted the interest of neuroscientists. In fact, 5-HT6 re- ceptors showed a high affinity for both typical (chlorpromazine, amoxapine) and atypical (clozapine, olanzapine) antipsychotics [4- 6]. Moreover, they influence acetylcholine release in the frontal cortex [7] and, for this reason, it has been hypothesized that they could be involved in cognition deficits and even in anxiety disor- ders [8]. Therefore, some 5-HT6 receptor ligands entered the clinical de- velopment as potential antipsychotics, antidementia agents [9-15] and anti-obese drugs [16], and other potential therapeutic applica- tions have also been suggested [17]. In this paper we present a comprehensive review of the avail- able data on 5-HT6 receptors, with a particular focus on the possi- ble clinical use of their agonists/antagonists, together with the re- sults of some ongoing studies of our group focused on their distri- bution in the human brain that suggest other possible therapeutic applications. DISCOVERY AND CHARACTERIZATION OF 5-HT6 RE- CEPTORS The first discovery of 5-HT 6 receptors was inside NCB-20 cells, a clonal cell line composed by a hybrid of mouse neuroblastoma *Address correspondence to this author at the Dipartimento di Psichiatria, Neurobiolo- gia, Farmacologia e Biotecnologie, University of Pisa, via Roma, 67, I-56100 Pisa, Italy; Tel: +39 050 2219768; Fax: +39 050 2219787; E-mail: dmarazzi@psico.med.unipi.it N18TG2 and Chinese hamster 18-day embryonic brain explant [18- 21]. However, its pharmacological characteristics were unclear. Indeed, the binding of 5-HT was increased or decreased by the non- hydrolyzable guanosine-5'-triphosphate (GTP) analog, Gpp(nh)P [18, 10]. Subsequently, Conner and Mansour [20] reported that lysergic acid diethylamide (LSD) was a potent partial agonist in the adenylate cyclase assay, but could not displace bound [ 3 H]5-HT. In contrast, 8-OHDPAT, which is a 5-HT 1A/7 agonist, displaced [ 3 H]5- HT binding, but had no effect on 3'-5'-cyclic adenosine monophos- phate (cAMP). When ascorbic acid was used to stabilize 5-HT, no specific binding of [ 3 H]5-HT was found. Therefore, the binding studies produced data that did not match with the potencies achieved by mean of the 5-HT-activated cyclase assay. In 1994, Unsworth and Molinoff interpreted the previous result as features of the 5-HT 1C and 5-HT 4 subtypes. For these reasons, it could be not attributable to any known 5-HT receptor, and it was suggested that the neuroblastoma N18TG2 cells presented a 5-HT receptor sub- type with 5-HT 6 pharmacological characteristics [22]. The results began to be more consistent in 1993 when the 5- HT 6 receptor was cloned [4, 23]. This was carried out with PCR amplification by using cDNA prepared from rat striatal mRNA (St- B17). The receptor was radiolabelled with [ 125 I]LSD, [ 3 H]LSD or [ 3 H]5-HT in COS-7 or HEK cells, whose binding sites were unaf- fected by the presence of guanine nucleotides [4]. Some years later, some structure shift errors were described in the gene sequence cloned previously [4, 23, 24], but the affinity values of contrasting compounds for 5-HT 6 receptors seemed similar, with the exclusion of metergoline (Ki = 400 nM [6], 1996; Ki = 30 nM [4]). Subsequently, in cloned rat HEK-293 cells it was found that better binding values of 5-HT 6 receptors could be obtained at low temperatures, that [ 3 H]LSD and [ 3 H]5HT may differently interact with 5-HT 6 receptors, and that LSD behaved as a partial agonist at that level (Boess et al., 1997). Nevertheless, the affinity values of compounds for the 5-HT 6 receptors did not seem to be always con- gruent, for example, the Ki value of lisuride, ranged between 30 nM [25], and 1.3 nM [26]. Moreover, there are species differences in the behaviour of different compounds, e.g., LSD, unlike rat and human 5-HT 6 recep- tors [20, 25], behaves as a full agonist in mice. In addition, the ligand Ro 04-6790, which binds to rat and human 5-HT 6 receptors, failed to do so in cloned mouse 5-HT 6 receptors [27]. 1875-533X/13 $58.00+.00 © 2013 Bentham Science Publishers