-transparent.png){kind=logo}
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-2-methoxy-phenyl)-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 (pKi = 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 M1-M3 receptors. However, RS 67333 and RS 67506 did exhibit affinities for the sigma 1 (pKi = 8.9 and 7.9, respectively) and sigma 2 (pKi = 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 (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 11308 (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 micrograms 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.
R M Eglen, and
D W Bonhaus, and
L G Johnson, and
E Leung, and
R D Clark
June 2003,
Naunyn-Schmiedeberg's archives of pharmacology,
R M Eglen, and
D W Bonhaus, and
L G Johnson, and
E Leung, and
R D Clark
July 2001,
Pharmacology,
R M Eglen, and
D W Bonhaus, and
L G Johnson, and
E Leung, and
R D Clark
April 2010,
Pharmacological research,
R M Eglen, and
D W Bonhaus, and
L G Johnson, and
E Leung, and
R D Clark
August 1993,
The Journal of pharmacology and experimental therapeutics,
R M Eglen, and
D W Bonhaus, and
L G Johnson, and
E Leung, and
R D Clark
February 1995,
British journal of pharmacology,
R M Eglen, and
D W Bonhaus, and
L G Johnson, and
E Leung, and
R D Clark
June 1995,
The EMBO journal,
R M Eglen, and
D W Bonhaus, and
L G Johnson, and
E Leung, and
R D Clark
November 2004,
British journal of pharmacology,
R M Eglen, and
D W Bonhaus, and
L G Johnson, and
E Leung, and
R D Clark
September 1996,
Trends in pharmacological sciences,
R M Eglen, and
D W Bonhaus, and
L G Johnson, and
E Leung, and
R D Clark
January 2013,
Frontiers in aging neuroscience,
R M Eglen, and
D W Bonhaus, and
L G Johnson, and
E Leung, and
R D Clark
June 2004,
Naunyn-Schmiedeberg's archives of pharmacology,
