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Serotonin Receptor and Transporter Ligands – Current Status Current Medicinal Chemistry 2001, 8, 999-1034 999 Serotonin Receptor and Transporter Ligands – Current Status Seung Jun Oh1, Hyun-Joon Ha2,*, Dae Yoon Chi3 and Hee Kyung Lee1 1Department of Nuclear Medicine, Asan Medical Center, University of Ulsan, College of Medicine, 388-1 Pungnap-dong, Songpa-gu, Seoul 138-736, Korea 2Department of Chemistry, Hankuk University of Foreign Studies,Yongin, Kyunggi-Do 449- 791, Korea 3Department of Chemistry, Inha University, Younghun-dong, Nam-gu, Inchon, 402-751, Korea Abstract: The serotonin (5-HT) receptor system has 14 different subtypes classified by pharmacology and function. Many ligands are widely used for therapeutic and diagnostic purposes in some severe human diseases. Most of the ligands that are specific for each 5-HT receptor have distinctive chemical structures with regard to pharmacophore elements including 4-arylpiperazine, benzimidazole, benzamide, chroman, aminopyridazine, tetralin, and polycycles. However, their affinity and selectivity for 5-HT, dopamine and a 1 receptors depend on their substituents and linker spacers. 5-HT transporter inhibitors have also been developed as potential antidepressants. In contrast to classical tricyclic compounds, newly developed secondary amine derivatives such as paroxetine and tetralin show high binding affinity and selectivity. Radioisotope-labeled ligands have 11 11 18 also been developed, including [carbonyl- C]WAY 100635 for 5-HT1A receptor, [ C or F]ketanserine 125 123 derivatives for 5-HT2 receptor, [ I]DAIZAC for 5-HT3 receptor, and [ I]IDAM for 5-HT transporter, and these are accumulated in brain regions that are rich in the respective receptors. This review summarizes the recent development of 5-HT receptor- and transporter-specific ligands and their pharmacological properties on the basis of their chemical structures. INTRODUCTION studied with many high-affinity ligands, and the results have been well documented in early reviews [3,4]. Although The diverse pharmacological actions of serotonin (5- many ligands with subnanomolar affinity for serotonin hydroxytryptamine, 5-HT) have been the subject of intense receptors and serotonin transporter have been developed, study since its identification in 1936. These pharmacological more selective ligands with high affinity are required to actions include activation or inhibition of smooth muscle discriminate among structurally or pharmacologically similar movement and cardiac muscle movement, and activation or receptors for clinical applications. Thorough studies have led inhibition of exocrine and endocrine glands, cells of the to new or modified chemical structures to improve the hematopoietic and immune systems, and central and properties of known ligands. These selective ligands have peripheral neurons [1]. The actions of 5-HT have led to the distinctive chemical structures that depend on receptor identification of at least 14 different 5-HT receptors on the subtypes with different binding profiles. basis of operational (function, antagonism, location), transductional (G-protein, ion channel), and structural (gene In addition to serotonin receptors, serotonin transporter is sequence, chromosomal location) criteria. 5-HT receptors are localized on presynaptic axon terminals on serotonin neurons classified into 5 types, namely 5-HT1, 5-HT2, 5-HT3, 5- [5]. This site is a target for antidepressant drugs which are HT4 and 5-HT5 receptors, which are further divided into 14 serotonin transporter inhibitors based on the fact that different subtypes as shown in Fig. (1) [2]. Of these 14 depression is due to a deficiency of monoamines such as classes of 5-HT receptor, the 5-HT3 receptor has a unique noradrenaline or 5-HT at postsynaptic receptors [4]. place in pharmacological investigation not only because it is Therefore, more selective serotonin reuptake site inhibitors the only 5-HT receptor which is coupled to an ion channel, should be good therapeutic agents for depression. but also because its localization in the central nervous system (CNS) is distinct from those of other classes of 5-HT Many compounds with high in vitro affinity and receptors. Although 14 serotonin receptors have been selectivity for specific serotonin receptors sometimes show classified, their distributions and molecular structures are not different pharmacological profiles in vivo due to the yet clear. Among these receptors, 5-HT1-like, 5-TH2, 5-TH3, instability of these compounds against various enzymes and 5-HT4, and serotonin transporter have been extensively their impaired ability to pass through the blood-brain barrier. Therefore, in vivo testing is required for the development of ligands for therapeutic purposes. The use of a radiotracer *Address correspondence to this author at the Department of Chemistry, based on ligands with high affinity and selectivity may be Hankuk University of Foreign Studies, Yongin, Kyunggi-Do, 449-791, helpful for obtaining biological, pharmacological, and Korea; Telephone: 82-335-330-4369; Fax: 82-335-330-4639; E-mail: [email protected] pharmacokinetic information as well as for imaging the in 0929-8673/01 $28.00+.00 © 2001 Bentham Science Publishers Ltd. 1000 Current Medicinal Chemistry, 2001, Vol. 8, No. 9 Ha et al. 5-HT 5-HT4 5-HT 5-HT 5-HT 5-HT 5-HT 5-HT 5-HT 3 6 5A 5B 7 5-HT1A 5-HT1F 1E 5-HT1D 5-HT1B 5-HT2B 2C 2A Fig. (1). vivo serotonin receptor distribution in human and animal brains for 5-HT1A, 5-HT2, and 5-HT3 receptors. N In this review, we discuss the recent development of 1 4 ligands including radiotracers targeted to the specific N N (CH2)4 R serotonin receptors for 5-HT1A, 5-HT1B/1D, 5-HT2, 5-HT3, N 5-HT4 and 5-HT transporter along with their chemical structures and activities. O O N R= N 5-HT1A RECEPTOR LIGANDS O The existence of multiple serotonin receptor subsites in O mammalian brain tissue has stimulated research to identify 1; Buspirone 2; Gepirone selective agents as pharmacological tools to evaluate the role of these receptors in various pathological conditions [6]. The OCH3 5-HT1A receptor has been the subject of several studies since 1 4 it was shown to be involved in various physiological N N CH R functions, such as sleep, appetite, and sexual behavior, and 2 pathological status, such as anxiety and depression [7,8]. The 5-HT1A receptor has been cloned, and has been shown to have 421 amino acids with the transmembrane part O arranged in seven helices [9]. R= (CH2)3 N CH 1-Arylpiperazines are one of the most important classes of O N 5-HT1A receptor ligand. Structure-activity relationship O H (SAR) studies have focused on the highly active 4-(w- substituted alkyl)-1-arylpiperazines ( Ki values of 10-8 to 10- 3; NAN-190 4; WAY 100135 10 M ), where an amide or imide function is present at the w position of the alkyl chain. Examples include buspirone (1), gepirone (2), NAN-190 (3), WAY 100135 (4), WAY CH2 100635 (5) and flesinoxan (6), as shown in Fig. (2). N N Extensive SAR studies regarding these compounds have O shown that 5-HT1A affinity is influenced by the nature of the aryl group at N1 of the piperazine ring and the length of the alkyl chain at the N4 position. With regard to the role of the 5; WAY 100635 amide or imide moiety, some authors have indicated that the presence of the terminal amide fragment plays an important F role in stabilizing the 5-HT1A receptor-ligand complex by p- p or dipole interactions [10-14]. Others have suggested that H N the amide function is not required for binding with the N N receptor [15,16]. In fact, the exact physiochemical requirements of the amide or imide-like region have not been O O O fully explained. Furthermore, their selectivity between dopaminergic D2 and adrenergic a 1 receptors is also not yet 6; Flesinoxan clear because these receptors have a high degree of similarity, OH Fig. (2). 5-HT Receptor and Transporter Ligands Current Medicinal Chemistry, 2001, Vol. 8, No. 9 1001 R O N R n N N R n N O OCH3 7 8 9 n = 1 or 2 OH O O O O N R N R R O O 10 11 12 Fig. (3). with up to 45% homology in their amino acid sequences methoxy derivatives (14-16) at C-6, C-7, or C-8 [14,18,19]. [17]. This indicates that the distance between the methoxy group and the alkyl chain is important. Indeed, when the alkyl Several aromatic analogues (7-12) based on buspirone, chain is at C-1 of the tetralin nucleus, the ideal position for WAY series, and flesinoxan [Fig. (3)], have also been the methoxy group is C-5. When the alkyl chain is at C-2, a studied, and the results have shown that a tetralin moiety methoxy group at C-6 or C-7 (17,18) gives the highest gives the highest selectivity. With regard to the effect of the affinity for the 5-HT1A receptor [Fig. (4)]. Thus, the spatial position of the methoxy group on the tetralin nucleus, the 5- relationship between the methoxy group and the alkyl chain position (13) gave a higher affinity than the corresponding on the tetralin nucleus is very important [14,18,19]. The function of an alkyl chain as a spacer between the tetralin moiety and the terminal group in aryl piperazine N derivatives has also been studied. The highest affinity for 5- HT1A receptor was found in a compound (19) with a three- N carbon chain, while chain lengths of two (20) or four (21) 8 gave less affinity [Fig. (5)] [18,19]. 7 H3CO 13-16 6 CH3O 5 N N N n N H3CO 17 compd n IC50 (nM) H3CO N 19 1 0.5 20 0 140 N 21 2 15 18 Fig.
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