Identification of tris-(phenylalkyl)amines as new selective h5-HT_2B receptor antagonists

Abstract

A series of tris-IJphenylalkyl)amines was synthesized and evaluated for affinity to human 5-HT 2 receptors. In general, the compounds displayed high affinity (4 of 11 analogs had K i values < 10 nM) and good selectivity for the 5-HT 2B receptor vs. other 5-HT 2 receptors. Functional assays revealed that the compounds are 5-HT 2B antagonists.The 5-HT 2B receptor is involved in regulation of the CNS, gastric and intestinal motility and cardiovascular function. 5-HT 2B antagonists have been explored as potential pharmacotherapies for migraine, 1 irritable bowel syndrome, 2-4 pulmonary hypertension 5 and heart failure. 6 5-HT 2B receptor agonists display antidepressant activity and 5-HT 2B receptor activation is required for antidepressant actions of selective serotonin reuptake inhibitors (SSRI's). 7 However, 5-HT 2B agonism is known to be associated with the development of valvular heart disease (VHD) and as such is regarded as an anti-target in most drug discovery programs. [8][9][10] Despite the promise of 5-HT 2B antagonists as useful therapeutics, there are no 5-HT 2B antagonists that are clinically approved for the clinical indications mentioned previously. This is partly because many known ligands are not truly 5-HT 2B selective IJ5-HT 2B ligands often also have affinity for the related 5-HT 2A and 5-HT 2C receptors) and even when selective there are issues related to ADME properties of the compounds that prohibit clinical translational studies. Fig. 1 shows some selective 5-HT 2B antagonists that are commercially available; these compounds are predominantly used as biological tools. 11-14 The identification of new 5-HT 2B preferring scaffolds is critical in the pursuit of novel chemical entities that may be developed as useful 5-HT 2B antagonist therapeutics. We describe herein the serendipitous discovery of a new series of ligands bearing a tris-IJphenylalkyl)amine scaffold with high affinity and selectivity for the 5-HT 2B receptor. The ease of synthesis of this scaffold makes it particularly attractive for further structure-activity work to optimize 5-HT 2B affinity, selectivity and antagonist activity in the quest for 5-HT 2B antagonist drugs.Our research team has been investigating aporphines based on the natural product nantenine (see inset, Scheme 1) as ligands for the 5-HT 2A receptor and this program has resulted in the identification of a number of new aporphinebased 5-HT 2A antagonists. [15][16][17] As part of those efforts, we decided to investigate the importance of molecular rigidity of the aporphine template on 5-HT 2A antagonism. In that regard, we decided to explore whether the replacement of the N-methyl group of nantenine with an N-phenylalkyl moiety and concomitant increase in flexibility would affect 5-HT 2A antagonist activity. We considered that this approach might allow the ligands multiple possibilities for interaction of the receptor with N-phenylalkyl groups which seem to be important pharmacophoric recognition elements in 5-HT 2A ligands, thus leading to increase in 5-HT 2A receptor ...

Structure, Function, and Pharmaceutical Ligands of 5-Hydroxytryptamine 2B Receptor

“…In addition, in order to investigate whether the molecular rigidity of the aporphine template of nantenine affects the 5-HT 2A R antagonism, a series of tris-(phenylalkyl)amines with increased flexibility compared with nantenine were synthesized. Similarly, these tris-(phenylalkyl)amines were found to have a high affinity and selectivity, as well as antagonist activity to the 5-HT 2B R [143]. Among them, compound 28 (Figure 8) showed the best binding affinity to the 5-HT 2B R (K i = 4.1 nM, IC 50 = 1259 nM in calcium flux assay), with a > 30-fold selectivity over the 5-HT 2A R and the 5-HT 2C R [143].…”

“…Similarly, these tris-(phenylalkyl)amines were found to have a high affinity and selectivity, as well as antagonist activity to the 5-HT 2B R [143]. Among them, compound 28 (Figure 8) showed the best binding affinity to the 5-HT 2B R (K i = 4.1 nM, IC 50 = 1259 nM in calcium flux assay), with a > 30-fold selectivity over the 5-HT 2A R and the 5-HT 2C R [143].…”

“…Figure 8. Representative C4 phenyl aporphines(27) and tris-(phenylalkyl)amines (28) as 5-HT 2B R antagonists[142,143].…”

Pharmacophore-based tailoring of biphenyl amide derivatives as selective 5-hydroxytryptamine 2B receptor antagonists

“…5 Continuous research efforts have advanced several 5-HT 2B antagonists into clinical trials, however, there have been no 5-HT 2B antagonists clinically approved up to now. 6 This is mainly because of the insufficient selectivity displayed by reported 5-HT 2B antagonists against 5-HT 2 receptor subtypes. 7 In addition, the poor pharmacokinetic profiles of lead 5-HT 2B antagonists have hindered their clinical translational studies.…”