Pharmacological characterization of two novel and potent 5‐HT4 receptor agonists, RS 67333 and RS 67506, in vitro and in vivo

• Published in: British journal of pharmacology Vol. 115; no. 8; pp. 1387 - 1392
• Main Authors: Eglen, R.M., Bonhaus, D.W., Johnson, L.G., Leung, E., Clark, R.D.
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.08.1995; Nature Publishing
• Subjects: 5‐HT4 receptors; Animals; Binding, Competitive; Biological and medical sciences; Carbachol - pharmacology; Corpus Striatum - drug effects; Corpus Striatum - metabolism; Esophagus - drug effects; Esophagus - metabolism; Guinea Pigs; Heart Rate - drug effects; In Vitro Techniques; Medical sciences; Muscle, Smooth - drug effects; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Pharmacology. Drug treatments; Rats; Receptors, Dopamine D1 - drug effects; Receptors, Dopamine D1 - metabolism; Receptors, Dopamine D2 - drug effects; Receptors, Dopamine D2 - metabolism; Receptors, Muscarinic - drug effects; Receptors, Muscarinic - metabolism; Receptors, Serotonin - drug effects; Receptors, Serotonin, 5-HT4; RS 67333; RS 67506; Serotonin Receptor Agonists - pharmacology; Serotoninergic system; Swine; Swine, Miniature; In vivo; Agonist; Biological fixation; Intravenous administration; Animal; Affinity; Mechanism of action; In vitro
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1111/j.1476-5381.1995.tb16628.x

1 The pharmacology of two novel 5‐HT4 receptor agonists, RS 67333 (1‐(4‐amino‐5‐chloro‐2‐methoxy phenyl)‐3‐[1(n‐butyl)‐4‐piperidinyl]‐1‐propanone HC1) and RS 67506 (1‐(4‐amino‐5‐chloro‐2‐methoxy‐phenyl)‐3‐[1‐(2‐methyl sulphonylamino)ethyl‐4‐piperidinyl]‐1‐propanone HC1) have been assessed in vitro and in vivo. 2 RS 67333 and RS 67506 exhibited affinities (pK1 = 8.7 and 8.8, respectively) for the 5‐HT4 binding sites, labelled with [3H]‐GR 113808, in guinea‐pig striatum. The Hill coefficients from these displacement curves were not significantly different from unity. The compounds exhibited lower affinities (<6.0) at several other receptors including 5‐HT1A, 5‐HT1D, 5‐HT2A, 5‐HT2C, dopamine D1, D2 and muscarinic Mr‐M3 receptors. However, RS 67333 and RS 67506 did exhibit affinities for the σ (pK1 = 8.9 and 7.9, respectively) and a2 (pK1 = 8.0 and 7.3, respectively) binding sites. 3 At the 5‐HT4 receptor mediating relaxation of the carbachol‐precontracted oesophagus, RS 67333 and RS 7506 acted as potent (pEC50 8.4 and 8.6, respectively), partial agonists (intrinsic activities, with respect to 5‐HT were 0.5 and 0.6, respectively) with respect to 5‐HT. Relaxant responses to RS 67333 or RS 67506 were surmountably antagonized by GR 113808 (10 nM), with apparent affinities (pKB) of 9.1 and 9.0, respectively. RS 67333 and RS 67506 induced dose‐dependent increases in heart rate of the anaesthetized micropig (ED50 4.9 and 5.4 ug kg−1, i.v.), with maximal increases of 35 and 47 beats min−1, respectively. 4 RS 67333 and RS 67506, therefore, acted as potent, partial 5‐HT4 receptor agonists in vitro and in vivo. These compounds, by virtue of their high potency and selectivity, may have some utility in elucidating the physiological role of 5‐HT4 receptors.