Current
Drug Targets-CNS & Neurological Disorders, Volume 3, No. 1, 2004
Contents
Hot
Topic: Subtypes of the 5HT Receptor
Guest
Editors: Mark D. Tricklebank and Derek N. Middlemiss
5-HT1
Receptors Pp. 1-10
Laurence
Lanfumey and Michel Hamon
5-HT2
Receptors Pp. 11-26
J.E.
Leysen
5-HT3
Receptors Pp. 27-37
Brenda
Costall and Robert J. Naylor
5-HT4
Receptors Pp. 39-51
J. Bockaert, S. Claeysen, V. Compan and A. Dumuis
5-HT5
Receptors Pp. 53-58
D.L.
Nelson
5-ht6
Receptors Pp. 59-79
Marie L. Woolley, Charles A. Marsden and Kevin C.F. Fone
5-HT7
Receptors Pp. 81-90
David R. Thomas and Jim J. Hagan
Abstracts
[Back to top] 5-HT1
Receptors
Laurence Lanfumey and Michel Hamon
Among the seven classes of serotonin (5-hydroxytryptamine, 5-HT) receptors which have been identified to date, the 5-HT1 class is comprised of five receptor types, with the 5-HT1A, 5-HT1B and 5-HT1D characterized by a high affinity for 5-carboxamido-tryptamine, the 5-HT1E and 5-HT1F characterized by a low affinity for this synthetic agonist, and all five having a nanomolar affinity for the endogenous indolamine ligand. The genes encoding 5-HT1 receptors have been cloned in both human and rodents, allowing the demonstration that they all belong to the G-protein-coupled receptor super- family with the characteristic 7 hydrophobic (transmembrane) domain-containing amino acid sequence. All the 5-HT1 receptor types actually interact with Gai/Gao proteins to inhibit adenylyl cyclase and modulate ionic effectors, i.e. potassium and/or calcium channels. Probes derived from the knowledge of amino acid sequence of the receptor proteins and of nucleotide sequence of their encoding mRNAs allowed the mapping of all the 5-HT1 receptor types in the central nervous system and other tissues. For the last twenty years, both pharmacological investigations with selective agonists and antagonists and phenotypical characterization of knock-out mice have been especially informative regarding the physiological implications of 5-HT1 receptor types. This research ends notably with the development of triptans, whose agonist activity at 5-HT1B, 5-HT1D and 5-HT1F receptors underlies their remarkable efficacy as antimigraine drugs. Clear-cut evidence of the implication of 5-HT1 receptors in anxiety- and depression-like behaviours and cognitive performances in rodents should hopefully promote research toward development of novel drugs with therapeutic potential in psychopathological and dementia-related diseases.
[Back to top] 5-HT2
Receptors
J.E. Leysen
5-HT2 receptors are G-protein coupled receptors that currently comprise three subtypes: 5-HT2A, 5-HT2B and 5-HT2C receptors. The subtypes are related in their molecular structure, amino acid sequence and signaling properties. 5-HT2A and 5-HT2C receptors have a widespread distribution and function in the central nervous system. 5-HT2A and 5-HT2C receptor antagonism is a property of certain antipsychotic and antide- pressant drugs. 5-HT2B receptors have a restricted expression in the central nervous system. They have an important role in embryogenesis and in the periphery. In this article, selected aspects of 5-HT2 receptor research are reviewed for each subtype under three main headings : (i) genes, protein structure and receptor signaling; (ii) receptor localization with emphasis on the CNS and (iii) compounds.
The general discussion reflects on the reasons for the limited success in the clinic of 5-HT2 receptor subtype selective drugs.
[Back to top] 5-HT3
Receptors
Brenda Costall and Robert J. Naylor
5-HT3-receptor antagonists are highly selective competitive inhibitors of the 5-HT3-receptor with negligible affinity for other receptors. They are potent, rapidly absorbed and easily penetrate the blood-brain barrier; metabolized by the cytochrome P450-system with half-lifes varying from 3-10 hours. The compounds investigated so far do not modify normal behaviour in animals or man and are well tolerated over wide dose ranges, the most common side effects being headache or constipation. Clinical efficacy was first established in chemotherapy-induced emesis (and then in radiotherapy-induced and post-operative emesis), where 5-HT3-receptor antagonists set a new standard of antiemetic efficacy and tolerability. The 5-HT3 receptor antagonists, via a central and / or peripheral action, have been shown to reduce secretion and motility in the gut and possess clinical utility in irritable bowel syndrome, and possibly other visceral pain disorders. Their value in fibromyalgia is being evaluated. In preclinical behavioural assays they induce effects consistent with anxiolysis, improved cognition, anti-dopaminergic activity and use in drug abuse and withdrawal. There is some evidence that ondansetron may reduce alcohol consumption in moderate alcohol abusers but overall, 5-HT3 receptor antagonists seem to be of limited use in psychiatric disorders: where effects have been seen, they seem to be unusually sensitive to dose and stage of disease. Nevertheless, their antiemetic potential has been of great benefit to cancer patients and the possible extension of their use to bowel disorders may yet fulfil their initial exciting promise.
[Back to top] 5-HT4
Receptors
J. Bockaert, S. Claeysen, V. Compan and A. Dumuis
Serotonin 4 receptors (5-HT4Rs) were discovered 15 years ago. They are coded by a very complex gene (700Kb, 38 exons) which generates eight carboxy-terminal variants (a, b, c, d, e, f, g, n). Their sequences differ after position L358. Another variant is characterized by a 14 residue insertion within the extracellular loop 2. Highly selective potent 5-HT4 receptor antagonists and partial agonists which cross the blood-brain barrier have been synthesized, but a specific full agonist for brain studies is still missing.
Based on physiological and behavioral experiments, 5-HT4Rs may be targets to treat cognitive deficits, abdominal pain and feeding disorders. One 5-HT4R-directed drug (SL65.0155) is already in phase II to treat patients suffering from memory deficits or dementia.
[Back to top] 5-HT5
Receptors
D.L. Nelson
The 5-HT5 receptor family consists of two members designated as 5-HT5A and 5-HT5B. To date the 5-HT5A receptor has been identified in the mouse, rat, and human. The 5-HT5B receptor also is expressed in the mouse and rat, but not in the human where the coding sequence is interrupted by stop codons. Both receptors are essentially limited in distribution to the central nervous system (CNS), although the 5-HT5A receptor has also been found on neurons and neuronal-like cells of the carotid body. Within the CNS the 5-HT5A receptor shows a relatively broad distribution, while the 5-HT5B receptor has a very restricted distribution. The 5-HT5A receptor has been demonstrated to couple to G proteins, and the primary coupling appears to be through Gi/o to inhibit adenylyl cyclase activity. The 5-HT5 receptors have not been extensively characterized pharmacologically. Both receptors show their highest affinity for LSD, which appears to act as a partial agonist at the 5-HT5A receptor. Amongst agonist-like molecules, 5-CT (5-carboxamidotryptamine) also has high affinity and has greater potency and affinity at the 5-HT5A receptor than does 5-HT itself. Both [
Molecular
Therapy Intervention Prospects in Prostate Cancer
Pp.523-530
Yashraj D. Rege1 and Vivek M. Rangnekar
I]LSD and [3H]5-CT have been used as radioligands to study the receptors in vitro. Nothing is known about the role of the 5-HT5B receptor in vivo. A mouse line has been developed where the 5-HT5A receptor has been knocked out and these animals have been shown to have a diminished response to LSD-induced increases in locomotion. The 5-HT5 receptors remain as two of the least studied and understood of the 5-HT receptor subtypes.
[Back to top] 5-ht6
Receptors
Marie L. Woolley, Charles A. Marsden and Kevin C.F. Fone
The 5-hydroxytryptamine6 (5-ht6) was one of the most recent additions to the 5-HT receptor family, selective antagonists have recently been developed and potential functional roles are now becoming apparent. The high affinity of a wide range of psychiatric drugs for the 5-ht6 receptor, together with its almost exclusive expression in the CNS, being abundant in limbic and cortical regions, has stimulated significant research interest. The 5-ht6 receptor appears to regulate glutamatergic and cholinergic neuronal activity, and increasing evidence suggests that it may be involved in the regu- lation of cognition, feeding and, possibly, affective state and seizures. The current article will review all aspects of the discovery, genetics, distribution, pharmacology and function of the 5-ht6 receptor. Taken together, this wealth of information warrants the use of the upper case nomenclature for the 5-ht6 receptor to be approved and its true status recognised.
[Back to top] 5-HT7 Receptors
David R. Thomas and Jim J. Hagan
Following the cloning of the 5-HT7 receptor in 1993, studies to investigate 5-HT7 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-HT7 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-HT7 receptor in the circadian pacemaker function of the suprachiasmatic nucleus (SCN), additional studies to investigate 5-HT7 receptor function in other brain regions have, until recently, been hindered by the absence of 5-HT7 receptor-selective ligands.
More recently, a number of 5-HT7 receptor-selective antagonists including, SB-269970-A and SB-656104-A have been developed. Studies utilising these compounds suggest that the 5-HT7 receptor modulates neuronal function in a number of brain areas including the hippocampus and thalamus. In turn, these findings suggest that 5-HT7 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-HT7 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-HT7 receptor or whose profile of action includes an interaction with this receptor.