Current Drug Targets-CNS & Neurological Disorders - Volume 3, Issue 1, 2004

Among the seven classes of serotonin (5-hydroxytryptamine, 5-HT) receptorswhich have been identified to date, the 5-HT1 class is comprised of five receptor types,with the 5-HT1A, 5-HT1B and 5-HT1Dcharacterized by a high affinity for 5-carboxamidotryptamine,the 5-HT1E and 5-HT1F characterized by a low affinity for this syntheticagonist, 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 superfamilywith the characteristic7hydrophobic(transmembrane) domain-containing amino acid sequence. All the5-HT1 receptor types actually interact with Gαi / Gαoproteins to inhibit adenylyl cyclase and modulate ioniceffectors, i.e. potassium and / or calcium channels. Probes derived from the knowledge of amino acid sequence ofthe 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, bothpharmacological investigations with selective agonists and antagonists and phenotypical characterization ofknock-out mice have been especially informative regarding the physiological implications of 5-HT1 receptortypes. This research ends notably with the development of triptans, whose agonist activity at 5-HT1B, 5-HT1Dand 5-HT1F receptors underlies their remarkable efficacy as antimigraine drugs. Clear-cut evidence of theimplication of 5-HT1 receptors in anxiety- and depression-like behaviours and cognitive performances inrodents should hopefully promote research toward development of novel drugs with therapeutic potential inpsychopathological and dementia-related diseases.

5-HT2 receptors are G-protein coupled receptors that currently comprise threesubtypes: 5-HT2A, 5-HT2B and 5-HT2C receptors. The subtypes are related in theirmolecular structure, amino acid sequence and signaling properties. 5-HT2A and 5-HT2Creceptors 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 antidepressantdrugs. 5-HT2B receptors have a restricted expression in the central nervous system. They have animportant role in embryogenesis and in the periphery. In this article, selected aspects of 5-HT2 receptor researchare reviewed for each subtype under three main headings : (i) genes, protein structure and receptor signaling;(ii) receptor localization with emphasisontheCNSand(iii)compounds. Thegeneraldiscussion reflects on the reasons for the limited success in the clinic of 5-HT2 receptor subtypeselective drugs.

5-HT3-receptor antagonists are highly selective competitive inhibitors of the 5-HT3-receptor withnegligible affinity for other receptors. They are potent, rapidly absorbed and easily penetrate the blood-brainbarrier; metabolized by the cytochrome P450-system with half-lifes varyingfrom310hours.Thecompounds investigated so far do not modify normal behaviour in animals or man and are well tolerated over wide doseranges, the most common side effects being headache or constipation.Clinical efficacy was first established inchemotherapy-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, theyseem to be unusually sensitive to dose and stage of disease. Nevertheless, their antiemetic potential has beenof great benefit to cancer patients and the possible extension of their use to bowel disorders may yet fulfil theirinitial exciting promise.

Serotonin 4 receptors (5-HT4Rs) were discovered 15 years ago. They are codedby a very complex gene (700Kb, 38 exons) which generates eight carboxy-terminalvariants (a, b, c, d, e, f, g, n). Their sequences differ after position L358. Another variant ischaracterized by a 14 residue insertion within the extracellular loop 2. Highly selectivepotent 5-HT4 receptor antagonists and partial agonists which cross the blood-brain barrier have been synthesized, but a specific full agonist for brain studiesis still missing. Based on physiological and behavioral experiments, 5-HT4Rs may be targets to treatcognitive 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 ordementia.

The 5-HT5 receptor family consists of two members designated as 5-HT5A and5-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 wherethe coding sequence is interrupted by stop codons. Both receptors are essentiallylimited 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 the5-HT5B receptor has a very restricted distribution. The 5-HT5A receptor has beendemonstrated to couple to G proteins, and the primary coupling appears to be throughGi / o to inhibit adenylyl cyclase activity. The 5-HT5 receptors have not been extensivelycharacterized pharmacologically. Both receptors show their highest affinity for LSD, which appears to act as apartial agonist at the 5-HT5A receptor. Amongst agonist-like molecules, 5-CT (5-carboxamidotryptamine) alsohas high affinity and has greater potency and affinity at the 5-HT5A receptor than does 5-HT itself. Both[125I]LSD and [3H]5-CT have been used as radioligands to study the receptors in vitro. Nothing is known aboutthe role of the 5-HT5B receptor in vivo. A mouse line has been developed where the 5-HT5A receptor has beenknocked out and these animals have been shown to have a diminished response to LSD-induced increases inlocomotion. The 5-HT5 receptors remain as two of the least studied and understood of the 5-HT receptor subtypes.

The 5-hydroxytryptamine6 (5-ht6) was one of the most recent additions to the5-HT receptor family, selective antagonists have recently been developed and potentialfunctional roles are now becoming apparent. The high affinity of a wide range ofpsychiatric drugs for the 5-ht6 receptor, together with its almost exclusive expression inthe CNS, being abundant in limbic and cortical regions, has stimulated significantresearch interest. The 5-ht6 receptor appears to regulate glutamatergic and cholinergicneuronal activity, and increasing evidence suggests that it may be involved in the regulationof cognition, feeding and, possibly, affective state and seizures. The current article will review all aspectsof the discovery, genetics, distribution, pharmacology and function of the 5-ht6 receptor. Taken together, thiswealth of information warrants the use of the upper case nomenclature for the 5-ht6 receptor to be approved andits true status recognised.

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.