Novel antagonists of serotonin-4 receptors: Synthesis and biological evaluation of pyrrolothienopyrazines
Graphical abstract
Introduction
In the last decade, much effort has been directed toward understanding the functions1 of the various receptor subtypes of the neurotransmitter serotonin (5-hydroxytryptamine, 5-HT), with emphasis on the most recently discovered binding sites, that is, the 5-HT4, 5-HT5, 5-HT6 and 5-HT7 receptors.2, 3, 4, 5, 6, 7 Among these receptors, which are linked to stimulation of cAMP production, the 5-HT4 subtypes have sparked the interest of scientists and physicians8 because of their functional and physiological significance. Indeed, 5-HT4 receptors have been demonstrated to be modulators of neurotransmitter release in various neuronal populations in the central nervous system, including basalocortical cholinergic,9, 10 striatal dopaminergic11, 12 and hippocampal serotoninergic13 cells. In parallel, the 5-HT4 receptor has been implicated in cognitive performance,14, 15, 16, 17, 18, 19, 20, 21, 22 making it a potential therapeutic target for treatment of the cognitive deficits associated with Alzheimer’s disease. Additionally, though with some inconsistencies,23 the observations that 5-HT4 receptor antagonists such as 1-methyl-1H-indole-3-carboxylic acid 1-(2-methanesulfonylamino-ethyl)-piperidin-4-ylmethyl ester GR113808 (1), 1-butyl-4-piperidinylmethyl 8-amino-7-chloro-1,4-benzodioxan-5-carboxylate SB204070 (2), and N-[(1-butyl-4-piperidinyl)methyl]-3,4-dihydro-2H-[1,3]-oxazino[3,2-a]indole-10-carboxamide SB207266 (3) have shown anxiolytic-like action in various models of anxiety in the rat,24, 25 suggest another possible therapeutic application of 5-HT4 receptor ligands.
Considering the distribution (e.g., atrium, gut) and the roles of 5-HT4 peripheral receptors, various cardiac or gastrointestinal effects can also be anticipated for selective ligands.26, 27, 28, 29 Indeed, 5-HT4 receptor partial agonists such as tegaserod (4) and prucalopride (5)30 are being developed for the management of irritable bowel syndrome. However, there exist only a limited number of high-affinity ligands selective for 5-HT4 receptors31 (Chart 1). When we began this work, very little was known about structure–activity relationships (SAR) of the 5-HT4 receptor ligands. Among the 5-HT4 receptor antagonists (Chart 2), tropisetron32 (6) was the first compound available; it exhibits low affinity for 5-HT4 receptors (pKi = 6.5) and high affinity for 5-HT3 receptors (pKi = 10). The second generation of ligands consisted of compounds such as endo-8-methyl-8-azabicyclo[3.2.1]oct-3-y1-2,3-dihydro-6-methoxy-2-oxo-1H-benzimidazole-1-carboxylate DAU6285 (7) possessing an equivalent affinity for 5-HT3 and 5-HT4 receptors.31 For compounds of the third generation, such as 2-diethylaminoethyl-[2-methoxy-4-amino-5-chloro] benzoate SDZ205557 (8), (1-S,8-S)-N-[(hexahydro-1H-pyrrolizin-1-yl)methyl]-6-chloroimidazo[1,2-a]pyridine-8-carboxamide33, 34 SC53606 (9), or 2-piperidinopropyl 4-amino-5-chloro-2-methoxybenzoate35, 36 RS23597 (10), the selectivity ratio toward 5-HT4 was greatly improved compared to 5-HT3 receptors, but these compounds remained insufficiently selective toward other receptors to be used as references. Finally, compounds 1 and 2 emerged as the first selective and high-affinity 5-HT4 receptor antagonists37, 38 (e.g., for 1, pKi = 9.5 toward 5-HT4 receptors; pKi < 6 toward 5-HT3 receptors).
The search for potent and selective 5-HT ligands has been ongoing in our laboratory for several years. The 5-HT3 receptor ligands have caused a huge interest in this receptor due to their potential therapeutic applications in a number of areas: emesis, anxiety, psychotic disorders, drug abuse, depression, migraine, pain, irritable bowel syndrome.39 We previously reported the synthesis, receptor binding profiles, and in vitro and in vivo pharmacological evaluation of several tricyclic series of piperazinopyrrolothienopyrazine, piperazinopyrido-pyrrolopyrazine, piperazinopyrroloquinoxaline and piperazinopyridopyrroloquinoxaline derivatives having high affinity, good selectivity, and partial agonist activity toward 5-HT3 receptors.40, 41 A 3D-QSAR study led to a precise definition of the pharmacophore for these partial 5-HT3 agonists42 (Fig. 1). The hypothesis that these compounds possess several characteristics in common with the 5-HT3 antagonists and also with 5-hydroxytryptamine itself, in terms of functional groups, was validated.
Furthermore, we developed a definition of a pharmacophore for the 5-HT4 receptor antagonists (Fig. 2) by considering a 3D-QSAR study starting from 15 antagonists described in the literature.43 In light of these two studies, and after a comparison between the two pharmacophores (partial 5-HT3 agonists and 5-HT4 antagonists), we formulated the hypothesis that it should be possible to transform a 5-HT3 ligand into a 5-HT4 ligand. This was the basis of our study of pharmacomodulation43 starting from 5-(4-benzylpiperazin-1-yl)pyrrolo[1,2-a]thieno[3,2-e]pyrazine39 S21007 (11). We also successfully used this pharmacophore to design benzo[h][1,6]naphthyridine and azepino[3,2-c]quinoline derivatives44 (12) by considering the bioisosteric replacement of the ester function [the hydrogen bond acceptor (HBA) component of the 5-HT4 pharmacophore] by a cyclic iminoether (see Chart 3).
We are now reporting in this paper the most recent results we obtained for the pharmacomodulation of the pyrrolothienopyrazine core by considering the 5-HT4 receptor antagonist pharmacophore as the starting point. On the basis of the potential therapeutic interest associated to selective 5-HT4 receptor ligands but also to bipotent 5-HT3/5-HT4 receptor ligands, the 5-HT3/5-HT4 receptor selectivity of our best derivatives will be assessed.
Section snippets
Chemistry
The new 5-substituted pyrrolo[1,2-a]thieno[3,2-e]pyrazines 31a–u, 32a–32n, 5-substituted pyrrolo[1,2-a]thieno[2,3-e]pyrazines 33a–f and 1-methyl-5-substituted pyrrolo[1,2-a]thieno[2,3-e]pyrazines 34a–k are shown in Table 1, Table 2, Table 3, Table 4. The general synthetic procedures used for their preparation are illustrated in Scheme 1. These compounds were obtained40 from 5-chloropyrrolo[1,2-a]thieno[3,2-e]pyrazine (28), 5-chloropyrrolo[1,2-a]thieno[2,3-e]pyrazine (29), and
Conclusion
We described a new family of compounds, pyrrolothienopyrazine derivatives, with high affinity for 5-HT4 receptors. We have demonstrated that it is possible to transform 5-HT3 ligands into 5-HT4 ligands by the means of a slight pharmacomodulation. Thus, these compounds allowed us to validate the 5-HT4 receptor antagonist pharmacophore and provided some insights into the selectivity toward 5-HT3/5-HT4 receptors. However, we have not yet found all the structural features in our series which could
Chemistry
Each compound was characterized by elemental analysis, IR spectra and 1H and 13C NMR spectra. 1H NMR and 13C NMR spectra were recorded on a JEOL Lambda 400 MHz spectrometer. The values of chemical shifts (d) are reported in parts per million (ppm) while coupling constants are given in Hertz (Hz) (these data are reported only for the compounds tested in the pharmacological study). Melting points were determined on a Köfler bank. IR spectra were taken with a Genesis Series FTIR spectrophotometer.
Acknowledgments
We thank the CRIHAN (Centre de Ressources Informatiques de Haute Normandie) and the European Community (FEDER) for the molecular modeling software. The authors wish to thank Béatrice Rouzaire Dubois (Laboratoire de Neurobiologie Cellulaire et Moléculaire UPR 9040—CNRS, Gif sur Yvette, France) for providing us with the NG108-15 cells. For the financial support, we thank the “Conseil Régional de Basse-Normandie”.
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Present address: Cognition et impulsivité, EA3917, Université de Caen, 14032 Caen.
- ‡
Present address: GMPC, EA4259, Université de Caen, 5 rue vaubénard, 14032 Caen.