Mediation of 5‐hydroxytryptamine‐induced tachycardia in the pig by the putative 5‐HT 4 receptor

1 The pharmacological properties of RS 23597-190 (3-(piperdine-1-yl)-propyl-4-amino-5-chloro-2-methoxy benzoate hydrochloride) have been studied in vitro and in vivo.2 RS 23597-190 competitively antagonized 5-HT4 receptor-mediated relaxations of rat, carbachol precontracted oesophageal muscularis mucosae, (pA2 = 7.8 ± 0.1; Schild slope = 1.2 ± 0.2). Affinity estimates (-log KB) at 5-HT4 receptors using either renzapride or SC-53116 as agonists yielded a -log KB value of 8.0 ± 0.01. In contrast, RS 23597-190 failed to antagonize contractile responses to 5-HT of guinea-pig ileal 5-HT3 receptors, even at concentrations up to 10 tiM. 3 Increases in short-circuit current, induced by 5-HT, were studied in guinea-pig ileal mucosal sheets. Concentration-response curves to 5-HT were biphasic, with the high potency phase to 5-HT inhibited by RS 23597-190 and mimicked by 5-methoxytryptamine. The -log KB value for RS 23597-190 at the high potency phase was 7.3 confirming that 5-HT4 receptors mediated the high potency phase. min. Transient arrhythmic effects were noted after administration of the compound. 7 In conclusion, RS 23597-190 acts as a high affinity, selective competitive antagonist at 5-HT4 receptors. Thus, the compound appears to be a useful tool for 5-HT4 receptor identification in vitro. In vivo, the compound is rapidly metabolized in pigs such that 5-HT4 blockade is not maintained. However, in the rat, when given by infusion, RS 23597-190 antagonizes 5-HT3 mediated responses, at doses consistent with a low affinity 5-HT3 receptor. These data suggest that, under appropriate experimental conditions, RS 23597-190 may also be used in vivo to characterize further 5-HT4 receptor function.

Section: Analysis Of Datamentioning

confidence: 99%

Section: In Vivo Studiesmentioning

confidence: 99%

RS 23597‐190: a potent and selective 5‐HT₄ receptor antagonist

Eglen¹,

Bley²,

Bonhaus³

et al. 1993

“…The method used was that described by Villalon et al (1990), modified according to Eglen et al (1993a;1994a,b (Cheng & Prusoff, 1973). Saturation binding studies were conducted with ten concentrations of radioligand.…”

Section: Tachycardia In Anaesthetized Micropigmentioning

confidence: 99%

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

Eglen¹,

Bonhaus²,

Johnson³

et al. 1995

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-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 (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-HTA, 5-HTID, 5-HT2A, 5-HT2c, dopamine D,, D2 and muscarinic M,-M3 receptors. However, RS 67333 and RS 67506 did exhibit affinities for the a, (pKi=8.9 and 7.9, respectively) and Ca2 (pK,=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 (pECm 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 pg kg-',i.v.), with maximal increases of 35 and 47 beats min-', 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.

“…In the periphery, 5-HT4 receptors produce a variety of responses including relaxation of smooth muscle (Reeves et al, 1991), neuronal cholinergically mediated contraction of guinea-pig ileum and proximal colon (Eglen et al, 1990;Elswood et al, 1991), enhancement of the 'twitch' response in electrically field stimulated guinea-pig ileum (Craig & Clarke, 1990) and induction of chloride secretion in rat distal colon . 5-HT4 receptors have also been implicated in cardiovascular effects in both pig and man (Bom et al, 1988;Villalon et al, 1990: Kaumann et al, 1990.…”

Section: Introductionmentioning

confidence: 99%

Development of a radioligand binding assay for 5‐HT₄ receptors in guinea‐pig and rat brain

Grossman¹,

Kilpatrick²,

Bunce³

1993

286

170

1 The 5-HT4 receptor antagonist, GRI13808, has been radiolabelled to a high specific activity with tritium. antagonists acting at the 5-HT4 receptor but not by compounds selective for other 5-HT receptors or other neurotransmitter receptors. 5 Autoradiographic analysis revealed a discrete localization in both guinea-pig and rat brain with high concentrations of binding in brain areas such as the striatum, substantia nigra and olfactory tubercle. 6 [3H]-GR113808 binding to homogenates of guinea-pig striatum meets the criteria for labelling of the 5-HT4 receptor and, as such, represents the first characterization of this receptor in a radioligand binding assay.