5-HT7 receptor antagonists

Recently, SB-269970 (l-[3-hydroxy-phenyl-sulphonyl]-2-[2-(4-methyl-l-piperidinyl)-ethyl] pyrrolidine) and SB-656104 (6-((R)-2- 2-[4-(4-chloro-phenoxy)-piperidin-l-yl]-ethyl pyrrolidine-l-sulphonyl)-lH-indole) have been reported to be potent 5-HT7 receptor antagonists (Hagan et al., 2000 Forbes et al., 2002). Selective 5-HT7 receptor agonists are not available at the present time. Systemic administration of SB-269970 or SB-656104 to rats at the beginning of the light period has been shown to reduce the total amount of REMS and to increase REMS latency. Values of W and SWS were not significantly modified (Hagan et al., 2000 Thomas et al., 2003). Hedlund et al. (2005) established that 5-HT7... 

Monti, J. M. Jantos, H. (2006a). Effects of the 5-HT7 receptor antagonist SB-269970 microinjected into the dorsal raphe nucleus on REM sleep in the rat. Behav. 

Roberts C, Allen L, Langmead CJ, Hagan JJ, Middlemiss DN, Price GW. The effect of SB-26,9970, a 5-HT7 receptor antagonist, on 5-HT release from serotonergic terminals and cell bodies. Brit. J Pharmacol 2001 132 1574-1580. 

The above-outlined results seemed to identify the 5-HT4 receptor as the sub-type responsible for the serotonin-induced suppression of the sAHP. However, subsequent experiments conducted in the CA3 region of the hippocampus indicated that saturating concentrations of the 5-HT4 antagonist GR-113808 could not completely suppress the 5-HT-induced reduction in the AHP. Equally surprising, the administration of 5-CT, which displays little affinity for 5-HT4 receptors, mimicked the effect of serotonin on the sAHP (12). These results pointed out to the involvement of a second 5-HT receptor subtype in the modulation of the sAHP. A careful pharmacological analysis of this response, including the use of the then newly developed selective 5-HT7 receptor antagonist... 

Blockade of the 5-HT7 receptor has been shown to reduce epileptic activity in animal models. Audiogenic seizures induced in DBA/2J mice could be prevented by drugs in a rank order of potency corresponding to their affinity for the 5-HT7 receptor (95). The selective 5-HT7 receptor antagonist SB-258719 has been shown to reduce epileptic activity in an animal model for absence epilepsy, the WAG/Rij rat (65). It is believed to do so by modulating the pacemaker current Ih within the thalamus (96,97). The 5-HT7 receptor has been demonstrated to mediate depolarization within the anterodorsal thalamus by increasing lh through a cAMP-dependent, PKA-independent mechanism (96,97). 

Forbes IT, Dabbs S, Duckworth DM, et al. (i )-3,Ar-dimethyl-Ar-[l-methyl-3-(4-methyl-piperidin-l-yl) propyl]benzenesulfonamide the first selective 5-HT7 receptor antagonist. J Med Chem 1998 41 655-657. 

Thomas DR, Melotto S, Massagrande M, et al. SB-656104-A, a novel selective 5-HT7 receptor antagonist, modulates REM sleep in rats. Br J Pharmacol 2003 139 705-714. 

Meneses A. Effects of the 5-HT7 receptor antagonists SB-269970 and DR 4004 in autoshaping Pavlovian/instrumental learning task. Behav Brain Res 2004 155 275-282. 

A series of diamino-1,3,5-triazines 41 have been identified as novel 5-HT7 receptor antagonists <04BMCL4245>. New 4,6-disubstituted 2-alkyl-l,3,5-triazines 42 and 43 showed interesting anticancer properties in different tumor cell lines <04JMC4649>. 

Pouzet B. SB-258741 a 5-HT7 receptor antagonist of potential clinical interest. CNS Drug Rev 2002 8 90-100. 

The 5-HT7 receptor is the most recently identified member of the family of G-protein-coupled 5-HT receptors. Although there is no selective agonist or antagonist currently available for the 5-HT7 receptor, the distinct pharmacological profile of 5-HT7 receptor sites has been used to delineate the function and distribution of this... 

Risperidone has been developed as a combined D2/5-HT2A receptor antagonist. In addition, it has a high affinity for 5-HT1A and 5-HT7 receptors. Whether such an effect has any relevance to its beneficial effects on the negative symptoms of schizophrenia, and lack of extrapyramidal side effects at moderate therapeutic doses, is unknown. An important advantage of risperidone over clozapine lies in its lack of antagonism of muscarinic receptors. 

Pharmacologically induced epileptiform activity in hippocampus slices can be used to assess the effect of 5-HT receptor-subtype-selective agonists and antagonist on network activity. To date, two studies have used this approach to understand how 5-HT4 and 5-HT7 could regulate hippocampal network activity (15,16). Activation of either 5-HT4 (15) or 5-HT7 (16) receptors increased coordinated epileptiform activity in this preparation, whereas activation of 5-HT1A receptors, which are also expressed in the hippocampus, suppressed it. The increases elicited by 5-HT4 and 5-HT7 receptors are consistent with those that could be predicted from the ability of these receptors to inhibit the sAHP in pyramidal cells (15,16). 

Constitutive activity of G protein-coupled receptors is a relatively new notion mainly described in recombinant receptor systems (29), but also in living animals (30). Such activity has been described for the 5-HT7 receptor when expressed in cell lines (24,31,32). A drug that inhibits constitutive activity is called an inverse agonist, and it has been reported that the selective antagonists SB-258719, SB-258741, and SB-269970 act as inverse agonists to a varying degree in vitro. It remains to be determined if constitutive activity is of relevance for the 5-HT7 receptor in vivo. 

---