The Serotonin 5-HT4 Receptor. 1. Design of a New Class of Agonists and Receptor Map of the Agonist Recognition Site

Abstract

The design and synthesis of a new class of potent and selective 5-HT4 receptor agonists containing an indole nucleus linked to a carbazimidamide are presented. A conformational study of the 5-HT4 receptor agonists serotonin and zacopride led to the identification of an initial pharmacophore and to the definition of a three-dimensional map of the 5-HT4 agonist recognition site. 1, a representative member of our new class of 5-HT4 receptor agonists, incorporates all reference structural features and matched perfectly with these models. 1 is a highly potent, full agonist at 5-HT4 receptors present in the isolated electrically stimulated guinea pig ileum preparation, with a pD2 value of 8.8, displaying selectivity (ranging from 40- to over 10,000-fold) versus other members of the serotonin receptor family.

Review of 5-HT4R Ligands: State of Art and Clinical Applications

“…14) The quinazolines 74, 75 and 76 were described as 5-HT 4 R agonists in a patent [129], with nanomolar affinities (K i = 55 nM for 74, 35 nM for 75) and agonist activities described by EC 50 Indole Carbazimidamide Derivatives (Fig. 15) A number of substituted indole carbazimidamides were evaluated as 5-HT 4 R agonists [130,131]. Compounds 77 and 78 were found to be very potent, full 5-HT 4 R agonists (EC 50 = 0.5 nM and 0.8 nM, respectively), being respectively 6 and 4 times more potent than 5-HT itself.…”

Serotonin Receptors, Type 4: A New Hope?

“…Among them, the indoles GR 113808 and GR 125487 [18,19], together with the benzoate SDZ 205557 [20], have proved to constitute highly potent and selective 5-HT 4 blockers. Similarly, complex derivatives of substituted benzamide function, such as RS 67333, or of indole function, such as tegaserod, are selective 5-HT 4 agonists [21,22], as is the benzofurane prucalopride [23]. Indeed, fifteen years only after the identification of 5-HT 4 receptors, there were already more than a dozen of selective pharmacological agents available to address their role and function [5].…”

A Single Mutation in the 5-HT4 Receptor (5-HT4-R D100(3.32)A) Generates a Gs-coupled Receptor Activated Exclusively by Synthetic Ligands (RASSL)

“…The demonstration that tryptamines and benzamides have different pharmacophores (14) prompted us to generate mutant 5-HT 4 receptors with the aim of disrupting the 5-HT recognition site, keeping the recognition site for synthetic 5-HT 4 agonists. 4(a) Receptor cDNA-The mutant was generated by exchanging the endogenous residue Asp 100 to Ala in the m5-HT 4(a) R cDNA sequence with the QuikChange site-directed mutagenesis kit (Stratagene).…”