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

• Published in: British journal of pharmacology Vol. 115; no. 6; pp. 1087 - 1095
• Main Authors: Hegde, S.S., Bonhaus, D.W., Johnson, L.G., Leung, E., Clark, R.D., Eglen, R.M.
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.07.1995; Stockton Press; Nature Publishing
• Subjects: 5‐HT4 antagonist; Administration, Oral; Animals; Biological and medical sciences; Colon - drug effects; colorectal distension; Dioxanes - pharmacology; Dose-Response Relationship, Drug; Esophagus - drug effects; Guinea Pigs; guinea‐pig colon; Indoles - pharmacology; Life Sciences & Biomedicine; Male; Medical sciences; Mice; mice diarrhoea; micropig tachycardia; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Piperidines - pharmacology; Radioligand Assay; rat oesophagus; Rats; Rats, Sprague-Dawley; RS 39604; SB 204070; Science & Technology; Serotonin - pharmacology; Serotonin Antagonists - pharmacology; Serotoninergic system; short‐circuit current; Sulfonamides - pharmacology; Time Factors; visceral pain; 5-HT4 ANTAGONIST; RAT; 5-HYDROXYTRYPTAMINE; RAT ESOPHAGUS; GUINEA-PIG; AGONISTS; SHORT-CIRCUIT CURRENT; VISCERAL PAIN; PIG ILEAL MUCOSA; RESPONSES; SE 204070; GUINEA-PIG COLON; MICROPIG TACHYCARDIA; MICE DIARRHEA; COLORECTAL DISTENSION; RS 39604; In vivo; Animal; Oral administration; Antagonist; In vitro; Biological activity; Comparative study
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1111/j.1476-5381.1995.tb15922.x

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 <6.5) for 5‐HT1A, 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.