RS 39604: a potent, selective and orally active 5‐HT4 receptor antagonist

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Abstract
1 Selective antagonism of 5-HT4 receptors may provide therapeutic benefit in certain disorders of the myocardium, alimentary and lower urinary tract. We now report on RS 39604, a novel and selective 5-HT4 receptor antagonist and compare its pharmacological properties with those of SB 204070. 2 In guinea-pig striatal membranes, both RS 39604 and SB 204070 inhibited specific binding of [3H]-GR 113808 in a concentration-dependent manner yielding p Ki estimates of 9.1 and 10.9, respectively. RS 39604 displayed a low affinity (pKi 1A, 5-HT2C, 5-HT3, α1c, D1? D2, M1 M2, AT1 B1 and opioid u receptors and moderate affinity for σ1 (pK1 = 6.8) and σ2 (pK1 = 7.8) sites. 3 In the rat isolated oesophagus, precontracted with carbachol, RS 39604 (30–300 nM) behaved as a competitive antagonist towards 5-HT-induced relaxation (pA2 = 9.3; Schild slope =1.0). We and others have shown previously that SB 204070 behaves as an unsurmountable antagonist in this preparation (pA2-10.5). In the guinea-pig isolated ileal mucosa, RS 39604 (30 nM) antagonized 5-MeOT-induced increase in short-circuit current (pA2 = 9.1). 4 In anaesthetized vagotomized micropigs, RS 39604, administered by the i.v. or intraduodenal (i.duod.) route, produced dose-dependent inhibition of 5-HT-induced tachycardia (ID50 = 4.7 μg kg−1, i.v. and 254.5 ug kg−1, i.duod). At maximal doses of 30 μg kg−1, i.v. and 6 mg kg−1, i.duod., the inhibitory effects of RS 39604 lasted for more than 6 h. In this preparation, SB 204070 was as potent as RS 39604 by the i.v. route but was inactive by the intraduodenal route at doses up to 3 mg kg−1. 5 In conscious mice, RS 39604, administered by the i.p. or p.o. route, produced dose-dependent inhibition of 5-hydroxytryptophan (5-HTP)-induced diarrhoea (ID50 = 81.3 ug kg−1, i.p. and 1.1 mg kg−1, p.o.). In this assay, SB 204070 was inactive by the oral route at doses up to 30 mg kg−1. 6 In anaesthetized guinea-pigs, RS 39604 antagonized the contractile effect of 5-HT in the proximal colon by producing parallel, dextral displacement of the dose-response curve to 5-HT. The mean dose-ratios to 5-HT at 0.1 mg kg−1, i.v., 1 mg kg−1, i.v. and 10 mg kg−1, i.duod. were 4.6, 30.7 and 10.8, respectively. SB 204070 behaved as an unsurmountable antagonist in this assay. 7 In a model of visceral pain in conscious rats, RS 39604 (0.01-1 mg kg−1, i.v.) did not affect colorectal distension-induced increases in arterial pressure whereas morphine (1 mg kg−1, i.v.) produced significant inhibition of the response, implying that 5-HT4 receptors are not involved in nociception in this model. 8 The data suggest that RS 39604 is a high affinity and selective 5-HT4 receptor antagonist that is orally active and long-lasting in vivo. It is concluded that RS 39604 may be the preferable probe to use for investigating the physiological and pathophysiological role of 5-HT4 receptors in vivo.