PHARMACOLOGICAL CHARACTERIZATION OF 2 NOVEL AND POTENT 5-HT4 RECEPTOR AGONISTS, RS-67333 AND RS-67506, IN-VITRO AND IN-VIVO

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 HCl) and RS 67506 (1-(4-amino-5-chloro-3-methoxyphenyl)-3-[1-(2-methyl sulphonylamino)ethyl-4-piperidinyl]-1-propanone HCl) have been assessed in vitro and in vivo. 2 RS 67333 and RS 67506 exhibited affinities (pK(i) = 8.7 and 8.8, respectively) for the 5-HT4 binding sites, labelled with [H-3]-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 D-1, D-2 and muscarinic M(1)-M(3) receptors. However, RS 67333 and RS 67506 did exhibit affinities for the sigma(1) (pK(i) = 8.9 and 7.9, respectively) and sigma(2) (pK(i) = 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 67506 acted as potent (pEC(50) 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 (pK(B)) of 9.1 and 9.0, respectively. RS 67333 and RS 67506 induced dose-dependent increases in heart rate of the anaesthetized micropig (ED(50) 4.9 and 5.4 mu g 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.