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Artículo destacado 
Drugs of the Future Review Article Drug discovery targets: 5-HT6 receptor Shelley L. Davies, Jordi S. Silvestre, Xavier Guitart Prous Science, Provenza 388, Barcelona 08025, Spain e-mail: jsilvestre@prous.com CONTENTS
Abstract The serotonergic (5-HT) nervous system has been implicated in cognitive function and feeding behavior. At present, there are a number of compounds undergoing biological testing for 5-HT6 receptor antagonism. Preclinical data have confirmed potent and selective antagonism for several compounds in vitro at the rat and human 5-HT6 receptor. Favorable cognition-enhancing effects have been demonstrated in rats, with significant improvement in memory retention, consolidation and spatial learning. Therefore, 5-HT6 antagonism has been proposed as a promising approach for treating cognitive impairment associated with neuropsychiatric disorders (e.g., Alzheimer's disease, schizophrenia). Furthermore, these compounds facilitate a reduction in food intake, fat absorption and body weight in genetic and dietary models of obesity. This review summarizes the progress with 5-HT6 receptor antagonists as a therapeutic strategy for Alzheimer's disease- and schizophrenia-associated cognitive dysfunction and obesity. Serotonin is a vasoactive amine found widely throughout the body which acts on 5-hydroxytryptamine (5-HT) receptors. 5-HT receptors are divided into seven families (5-HT1 to 5-HT7) according to structural and functional homologies, with different subtypes in some families (1). This has facilitated the investigation of subtype-specific physiological/pathophysiological roles. Figure 1 illustrates the current therapeutic impact of 5-HT6 receptor antagonists. Tables I, II and III show the 5-HT6 receptor binding affinity of compounds from patents, compounds from the literature and antipsychotic agents, respectively. As can be seen, compounds with 5-HT6 receptor-antagonist properties have a predominantly sulfone or sulfonamide structure. A number of agents are undergoing biological testing for those conditions outlined in Figure 1, but in particular, preclinical data have been generated for several potent and selective 5-HT6 receptor antagonists as procognitive and antiobesity treatments. This review will therefore focus on the role of 5-HT6 receptors in cognition and feeding behavior and outline the experimental progress to date.
Fig. 1. Therapeutic impact of 5-HT6 receptor antagonists (from Prous Science Integrity®).
The 5-HT6 receptor as a target for cognitive dysfunction Alzheimer's disease and schizophrenia are associated with chronic and severe cognitive deficits. Alzheimer's disease is the most common cause of dementia in the elderly. This brain disorder is a slow disease that progresses as nerve cell damage, neuritic plaques and neurofibrillary tangles (2) extend to different parts of the brain that control thought, memory and language. Early symptoms include mild cognitive impairment with a decline in the ability to perform simple everyday tasks. Over time, patients can no longer think clearly or make judgements, language skills are diminished, and mood and personality changes may occur. Eventually, with severe brain atrophy they become completely unresponsive and require total care (3). It is a major health problem worldwide, with the incidence estimated to be between 15 and 18 million individuals. This is expected to increase to 45 million people by 2050 (4). In contrast, the symptoms of schizophrenia typically emerge in late adolescence or early adulthood, and often persist throughout the rest of the patient's life. This condition affects approximately 24 million people worldwide (5, 6). Although the etiology of schizophrenia is not well understood, in general, it is thought to be a disorder of developmental maturation rather than of neurodegeneration (7). Cognitive dysfunction, ranging from impaired attention to abnormal executive function, as well as depression and/or anxiety, may present prior to positive and negative symptoms, and can change over time. Although antipsychotic agents are commonly utilized in the treatment of schizophrenia, it is now thought that targeting cognitive deficits, the method for treating Alzheimer's disease, may generate more favorable outcomes. In the past, a great deal of emphasis has been placed on abnormalities within the cholinergic system as a focus for procognitive therapies for Alzheimer's disease and schizophrenia. However, cholinesterase inhibitors are associated with severe side effects and unsatisfactory results (8, 9). More recently, studies have identified an important role for 5-HT6 receptors in cognitive function. The 5-HT neuronal system projects to virtually every brain region that subserves cognition (10) and there is evidence indicating that a 5-HT system decline is associated with cognitive dysfunction (11). It has been shown that 5-HT6 receptor expression is abundant in brain regions associated with learning and memory, including the hippocampus, cerebral cortex and amygdala (12, 13). Prior to the development of selective 5-HT6 ligands, early studies identified the therapeutic potential of 5-HT6 receptor modulation for cognitive dysfunction via the use of antisense oligonucleotides designed to reduce the expression of 5-HT6 receptors. Intracerebroventricular injection of antisense oligonucleotides over 6 days to rats facilitated progressive enhancement of memory retention in the water maze memory task (14). Correspondingly, there is evidence for 5-HT6 receptor-mediated inhibitory control over acetylcholinesterase (15) and the induction of behaviors in rodents that are mediated by an increase in cholinergic neurotransmission in the CNS (16). Preclinical evidence for cognitive improvement via 5-HT6 antagonism is, however, contradictory and thought to be hindered by the diversity among 5-HT6 receptors in humans, rats and mice. Although 5-HT6 receptors share a high degree of homology (over 84%), differences in receptor profiles have been described in binding studies using [125I]-SB-258585. Although this radioligand displays high affinity for rat and human brain 5-HT6 receptors, a very low level of specific binding has been observed in the mouse brain (17). Further investigation has shown that 5-HT6 receptor expression is considerably lower in the mouse brain compared to rat and human brains, and while 5-HT6 receptors accumulate in the basal ganglia and limbic structures in rats and humans, expression is very low in the basal ganglia of mice. Distinct pharmacological profiles have also been demonstrated with differences in rat/human and mouse receptor residues for ligand binding to the 5-HT6 receptor (18). Therefore, it has been suggested that the evaluation of 5-HT6 receptor antagonist efficacy in mice should be interpreted with caution. The 5-HT6 receptor as a target for obesity Obesity refers specifically to the excessive accumulation of fat in adipose tissue, to the extent that health and wellbeing are adversely affected. Because obesity increases the risk for other health disorders, it has a major impact on mortality. Life span is often significantly reduced with the concurrent diagnosis of conditions including type 2 diabetes, hypertension, coronary heart disease, dyslipidemia, sleep apnea, blood clots and ischemic stroke (19, 20). It also increases the risk of several types of cancer (colon, endometrial, prostate and postmenopausal breast cancers), gallbladder disease, musculoskeletal disorders, pulmonary dysfunction, infertility in women and depression (21). Obesity has become a chronic problem among adults. The incidence has doubled since 1980, and the number of overweight adolescents has tripled. As treatment for this condition is often invasive, drugs that reduce energy intake, increase energy expenditure, decrease the absorption of fat or stimulate fat mobilization (22-24) would be important antiobesity pharmacotherapies. Early studies demonstrated that chronic administration of 5-HT6 receptor antisense oligonucleotides produced a significant reduction in food intake and body weight in rats (25). 5-HT6 receptor knockout mice are also resistant to weight gain when exposed to a high-fat diet (26). Experimental pharmacology of 5-HT6 receptor antagonists Binding data In vitro binding studies have demonstrated the different receptor binding profiles of 5-HT6 receptor antagonists (see Table II). The first selective 5-HT6 receptor antagonists, Ro-04-6790 and Ro-63-0563, were described by Roche. In binding assays with [3H]-LSD, these compounds displayed mean pKi values at the rat 5-HT6 receptor of 7.35 and 7.83, respectively, and pKi values at the human 5-HT6 receptor of 7.26 and 7.91, respectively. Both compounds were found to be over 100-fold selective for the 5-HT6 receptor relative to a panel of other receptor binding sites. However, brain permeability was extremely limited (< 1%) (27). This work led to the development of Ro-65-7674, which displayed good potency for the 5-HT6 receptor (pKi = 9.07) and high selectivity over a number of other binding sites (28, 29). Subsequent compounds were reported by the former SmithKline Beecham (now GlaxoSmithKline). SB-271046 displayed excellent 5-HT6 receptor affinity in transfected HeLa cells (pKi = 8.9), with > 200-fold selectivity over 50 other receptors, enzymes and ion channels (30). In experiments in native brain tissues using [3H]-LSD and [125I]-SB-258585 as radioligands, SB-271046 presented pKi values of 8.9 and 9.1, respectively. The compound also displaced [125I]-SB-258585 from rat and pig striatal and human caudate putamen membranes with pKi values of 9.02, 8.55 and 8.8, respectively, and over 200-fold selectivity for the human 5-HT6 receptor as compared to 55 other receptors, enzymes and ion channels (31). As described above, differences in affinity according to species have also been shown, as SB-271046 displays similar potency at the human and rat receptors but a 4-fold lower affinity for the mouse receptor (32). However, as SB-271046 showed low brain penetration, a derivative of this compound, SB-399885, was selected for further evaluation (33). SB-399885 displayed high affinity for both rat and human 5-HT6 receptors, with pKi values ranging from 8.81 to 9.11. Investigation of a further analogue, SB-357134, also demonstrated potent inhibition of [125I]-SB-258585 and [3H]-LSD binding in a HeLa cell line expressing human 5-HT6 receptors (pKi = 8.6 and 8.54, respectively). Furthermore, SB-357134 inhibited [125I]-SB-258585 binding in human caudate putamen and in rat and pig striatal membranes (pKi = 8.82, 8.44 and 8.61, respectively). The compound also displayed over 200-fold selectivity for the 5-HT6 receptor versus 72 other receptors and enzymes (34), and 4 h postadministration it inhibited ex vivo [125I]-SB-258585 binding in the rat with an ED50 of 4.9 mg/kg p.o. (34). In vivo studies established that oral SB-399885 binds specifically to the 5-HT6 receptor in the striatum of rats with an ED50 of 2 mg/kg (35). Scientists from Lilly also recently presented data on a newly developed, potent and selective 5-HT6 antagonist, diF-BAMPI, which binds to 5-HT6 receptors with a Ki value of 1.3 nM (36). Functional activity 5-HT6 receptors are positively coupled to adenylyl cyclase via Gs (37). In functional studies, neither Ro-04-6790 nor Ro-63-0563 had any significant effect on basal levels of cyclic AMP (cAMP) accumulation in HeLa cells expressing the human 5-HT6 receptor, suggesting that the compounds are neither agonists nor inverse agonists at this receptor. However, both Ro-04-6790 and Ro-63-0563 behaved as competitive antagonists, with mean pA2 values of 6.75 and 7.10, respectively (27). Functional analysis of the human cloned 5-HT6 receptor has demonstrated that SB-271046 competitively antagonizes 5-HT-dependent increases in cAMP, with a pA2 value of 8.71 (25). 5-HT-stimulated cAMP accumulation in cells expressing the human 5-HT6 receptor was also competitively antagonized by SB-357134 (pA2 = 7.63) (34). Furthermore, in vitro studies in HEK cells transfected with the human 5-HT6 receptor and using a chimeric G-protein (G-aq/G-as) revealed that the antagonist SB-271046 exerts a concentration-dependent antagonist effect on Ca2+ responses evoked by 5-HT, with an IC50 value of 11 nM (38). Neurochemistry In vivo microdialysis studies have demonstrated the neurochemical effects of 5-HT6 receptor antagonists in selected regions of the brain. Ro-65-7674 was proven to increase extracellular acetylcholine (ACh) content in the frontal cortex of freely moving rats at a dose of 30 mg/kg p.o. (28, 29). Interaction with monoaminergic receptors and a modest elevation in ACh efflux in the rat hippocampus have also been noted following administration of Ro-04-6790 (39). Administration of SB-271046 (10 mg/kg s.c.) produced a significant increase in extracellular levels of both glutamate and aspartate within the frontal cortex and hippocampus (40, 41). These neurochemical changes were tetrodotoxin-dependent but were not affected by coadministration of the muscarinic antagonist atropine, indicating on the one hand, an impulse-dependent origin, and on the other, that the enhanced excitatory neurotransmission observed was not a consequence of enhanced cholinergic function (41). The compound also evoked a significant increase in extracellular levels of dopamine and epinephrine in the prefrontal cortex, without altering 5-HT neurotransmission (42). Oral doses of 1, 3 or 10 mg/kg of SB-399885 increased the extracellular levels of noradrenaline, dopamine and ACh in the prefrontal cortex of freely moving rats (35). Metabolism, pharmacokinetics and tolerability In vitro studies have demonstrated that SB-271046 does not inhibit cytochrome (CYP) P-450 activity, which was confirmed in isoform-selective assays of major human isoenzymes (CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4) (30). Pharmacokinetic studies in rats demonstrated low brain permeability for the Roche compounds Ro-04-6790 and Ro-63-0563 (< 1%) (27, 30). SB-271046 and SB-357134 showed higher, although only moderate, brain permeability, reaching 10% (30) and 19% (34, 42), respectively. SB-271046 has a low blood clearance rate (7.7 ml/min/kg) and an adequate half-life (4.8 h), with over 80% oral bioavailability (30). The bioavailability of SB-357134 reached 65% (34, 43), and when administered at 10 mg/kg p.o., peak blood and brain concentrations were 4.3 and 1.3 mM, respectively, 1 h postadministration (34). Cognition studies Early studies demonstrated that Ro-04-6790 produced a behavioral response (stretching, yawning and chewing) similar to that seen following treatment with antisense oligonucleotides (27). Further investigation revealed that administration of nonselective muscarinic antagonists such as scopolamine and atropine inhibited stretching induced by Ro-04-6790. This indicates a useful functional correlation between cholinergic neurotransmission in the CNS and 5-HT6 receptor blockade (44). In cognition studies, whereas Ro-04-6790 (10 or 30 mg/kg i.p.) alone had no effect on performance on the novel object discrimination task, it completely restored the scopolamine-induced memory deficits (45), as did Ro-65-7674 (28, 29) and Ro-43-68554 (46). Further analysis of Ro-43-68554 demonstrated its activity in the reversal of object and social recognition deficits and in enhancing autoshape learning, whereas it was ineffective in the radial arm maze, step-through passive avoidance test and Morris water maze test in aged rats (46). The procognitive effects of SB-271046, which displays higher oral bioavailability and better brain penetration (25), have been investigated more extensively. In the rat, SB-271046 potentiated acetylcholinesterase inhibitor-induced behavior, facilitating cholinergic-mediated stretching, yawning and chewing (31, 32). Examination of spatial learning and memory in rats using a water maze demonstrated that oral administration of SB-271046 (10 mg/kg) improved retention, but it did not significantly alter learning facilitation. In contrast, the acetylcholinesterase inhibitor donepezil (0.1 and 0.3 mg/kg p.o.) had no effect, suggesting mechanisms independent of cholinergic neurotransmission in learning and memory processes (47). Further studies in aged rats receiving SB-271046 (0.3-0.6 mg/kg i.p.) over 3 days demonstrated equivalent dose-dependent improvements in retention performance (48). In contrast, another study which used SB-271046 at the optimal dose (10 mg/kg p.o.) failed to demonstrate any significant difference in memory acquisition or retention on water maze tasks (32). Behavioral analysis of object discrimination revealed that acute SB-271046 (10 mg/kg i.p.) administered prior to and after familiarization trials completely reversed time delay-induced deficits in object discrimination, as rats preferred to explore novel rather than familiar objects. This indicated that SB-271046 is capable of enhancing memory consolidation (49). These observations of retention efficacy were also demonstrated in a dose-ranging study in young and aged rats. At 0.3-10 mg/kg i.p., SB-271046 produced a significant and dose-dependent increase in novel object exploration in young rats, with similar results seen in aged rats at doses of 0.3-3.0 mg/kg i.p. In this case, similar results were also seen with donepezil (0.3-3.0 mg/kg p.o.) (48). The assessment of the efficacy of SB-271046 (0.3-10 mg/kg i.p.) in passive avoidance to footshock revealed a significant and complete reversal of memory deficits in aged rats, with equivalent results to donepezil (48). Subsequent studies in mature rats demonstrated that SB-271046 dose-dependently reversed scopolamine-induced amnesia in a passive avoidance paradigm, with significant effects at 3, 10 and 20 mg/kg p.o. Furthermore, chronic administration of SB-271046 enhanced spatial learning in aged animals in the water maze task and improved recall in the same task (50). Analysis of the SB-271046 analogues SB-399885 and SB-357134 revealed that these compounds (10 mg/kg) also improved memory retention (34, 35, 47) and learning (34) using water maze tasks, while also reversing memory impairment induced by scopolamine in a novel object recognition paradigm (35). Preliminary data recently presented on the behavioral effects of diF-BAMPI also demonstrated improved memory acquisition in rat models of cognition (36). Saegis Pharmaceuticals has reported on the effectiveness of SGS-518, its novel and selective 5-HT6 receptor antagonist, in behavioral studies of learning and memory. The compound also recently completed placebo-controlled, dose-ranging phase I clinical studies in healthy volunteers, indicating safety and good tolerability (51). Feeding behavior studies In vivo studies have also demonstrated a role for selective 5-HT6 receptor antagonists in the regulation of feeding. Ro-04-6790 administered i.p. to rats over 3 days (30 mg/kg) facilitated a reduction in body weight (52). Further studies have revealed a dose-related reduction in food consumption following acute administration of Ro-04-6790 (ID50 = 18.6 mg/kg) and SB-271046 (ID50 = 14.45 mg/kg) to rats accustomed to a fixed daily feeding regimen (53). BVT-5182 (3 mg/kg s.c.) potently reduced food intake in a genetic mouse model of obesity without affecting general motor activity or water intake. Chronic administration of BVT-5182 also reduced body weight and cumulative food intake by 9% and 11%, respectively, in mice fed a high-fat diet. 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Drugs of the Future Vol. 30, No. 5, 2005, pp. 479-495
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