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

Abstract

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.

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

“…These compounds are analogues of the selective 5-HT4 antagonist, RS 23597; a compound that lacks efficacy at 5-HT4 receptors in rat oesophagus, vagus nerve, guinea-pig ileum in vitro or micropig myocardium in vivo (Eglen et al, 1993b (Bonhaus et al, 1994). However, the potential interaction of these compounds with sigma sites in vitro or in vivo cannot be excluded.…”

“…at 5-HT4 receptors in rat isolated oesophagus, vagus nerve and guinea-pig ileum (Eglen et al, 1993b). In human isolated urinary bladder, however, RS 23597 acts as a partial agonist, albeit of low intrinsic efficacy (Rizzi et al, 1994, unpublished observations).…”

“…In the present study, we describe the pharmacology of two novel 5-HT4 receptor agonists, structurally related to the 5-HT4 antagonist, RS 23597 (Eglen et al, 1993b). The antagonist ( Figure 1) possesses moderate affinity (pKB=7.8)…”

“…RS 23597 is a substituted benzamide ester, and thus has limited duration of action in vivo as a result of plasma hydrolysis (Eglen et al, 1993b). In a medicinal chemistry programme designed to augment the in vivo stability of RS 23597, the ester function was replaced, resulting in a series of ketone analogues (Clark et al, 1994).…”

Systems pharmacology identifies drug targets for Stargardt disease–associated retinal degeneration

“…Antagonists of Gs-coupled 5-HT4R (RS), 5-HT6R (RO and SGS), and 5-HT7R (SB and LY), which are used to induce relaxation and treat cognitive impairments such as amnesia, anxiety, and depression in patients, were effective in protecting mouse retina only at high doses (Supplemental Table 2), in which possible side effects could pose a problem. For example, transient but severe electrocardiographic changes and episodes of premature ventricular contractions were observed in patients when RS was administered at a dose that effectively blocked the 5-HT4R activity associated with periods of electrical-mechanical dissociation, leading to severe hypotension due to impaired cardiac function (75). Among these receptors, 5-HT4R is most highly expressed in the human retina (Table 1).…”