Characterization of SB‐269970‐A, a selective 5‐HT₇ receptor antagonist

Abstract

1 The novel 5-HT 7 receptor antagonist, SB-269970-A, potently displaced [ 3 H]-5-CT from human 5-HT 7(a) (pK i 8.9+0.1) and 5-HT 7 receptors in guinea-pig cortex (pK i 8.3+0.2). 2 5-CT stimulated adenylyl cyclase activity in 5-HT 7(a) /HEK293 membranes (pEC 50 7.5+0.1) and SB-269970-A (0.03 ± 1 mM) inhibited the 5-CT concentration-response with no signi®cant alteration in the maximal response. The pA 2 (8.5+0.2) for SB-269970-A agreed well with the pK i determined from [ 3 H]-5-CT binding studies. 3 5-CT-stimulated adenylyl cyclase activity in guinea-pig hippocampal membranes (pEC 50 of 8.4+0.2) was inhibited by SB-269970-A (0.3 mM) with a pK B (8.3+0.1) in good agreement with its antagonist potency at the human cloned 5-HT 7(a) receptor and its binding anity at guinea-pig cortical membranes. 4 5-HT 7 receptor mRNA was highly expressed in human hypothalamus, amygdala, thalamus, hippocampus and testis. 5 SB-269970-A was CNS penetrant (steady-state brain : blood ratio of ca. 0.83 : 1 in rats) but was rapidly cleared from the blood (CLb=ca. 140 ml min 71 kg 71). Following a single dose (3 mg kg 71 ) SB-269970 was detectable in rat brain at 30 (87 nM) and 60 min (58 nM). In guinea-pigs, brain levels averaged 31 and 51 nM respectively at 30 and 60 min after dosing, although the compound was undetectable in one of the three animals tested.

Expression of 5-HT7 receptor mRNA in the hamster brain: Effect of aging and association with calbindin-D28K expression

“…For example, administration of the 5-HT 7 receptor-selective antagonists, SB-269970-A or DR-4004, to hamsters blocks phase advances of circadian locomotor activity rhythms induced by the serotonergic agonists, 8-OH-DPAT or 5-carboxamidotryptamine, demonstrating that pharmacological activation of 5-HT 7 receptors stimulates circadian phase resetting (Ehlen et al, 2001;Duncan et al, 2004). Also, administration of 5-HT 7 receptor-selective antagonists to guinea pigs or rats selectively decreases REM sleep, suggesting that endogenous serotonin acting at 5-HT 7 receptors exerts a tonic inhibition on REM sleep (Hagan et al, 2000;Thomas et al, 2003;Monti and Jantos, 2006). Furthermore, studies in mice have shown that deletion of the 5-HT 7 receptor gene impairs memory and learning (Roberts et al, 2004), reduces immobility in the Porsolt swim test, similar to antidepressants (Guscott et al, 2005;Hedlund et al, 2005), and inhibits hypothermia induced by 8-OH-DPAT (Hedlund et al, 2003).…”

“…The 5-HT 7 receptor subtype, the most recently cloned of the serotonin receptor subtypes, modulates many physiological and behavioral functions, including circadian rhythms (Ehlen et al, 2001;Duncan et al, 2004;, rapid eye movement (REM) sleep (Hagan et al, 2000;Thomas et al, 2003;Monti and Jantos, 2006), body temperature (Hedlund et al, 2003), learning and memory (Roberts et al, 2004), and behavior (Guscott et al, 2005;Hedlund et al, 2005). For example, administration of the 5-HT 7 receptor-selective antagonists, SB-269970-A or DR-4004, to hamsters blocks phase advances of circadian locomotor activity rhythms induced by the serotonergic agonists, 8-OH-DPAT or 5-carboxamidotryptamine, demonstrating that pharmacological activation of 5-HT 7 receptors stimulates circadian phase resetting (Ehlen et al, 2001;Duncan et al, 2004).…”

Role of 5-HT receptor mechanisms in sub-chronic PCP-induced reversal learning deficits in the rat

“…WAY-100635 has selective 5-HT 1A receptor antagonist activity at the doses used in this study (Prinssen et al, 1999). The doses of SB-269970A were selected based on pharmacokinetic analysis (Hagan et al, 2000), doses of SB-243213A (5-methyl-1- [[2-[92-methyl-3-pyridyl0oxy]-5-pyridyl]carbamoyl]-6-trifluoromethylindone hydrochloride) were selected based on effects observed in a study by Wood et al, (2001).…”

Building a Better Antipsychotic: Receptor Targets for the Treatment of Multiple Symptom Dimensions of Schizophrenia

“…31 It is still not conclusively known, however, whether and to what extent these actions contribute to therapeutic effects. Other potential roles for the 5-HT 7 receptor include regulation of circadian rhythms 28 and sleep, 32 thermoregulation, [33][34][35] learning and memory, 36,37 and endocrine regulation. 38,39 …”