Design, Synthesis, and Structure–Activity Relationships of Highly Potent 5-HT<sub>3</sub> Receptor Ligands

Verheij, Mark H.P.; Thompson, Andrew; Muijlwijk‐Koezen, Jacqueline E. van; Lummis, Sarah C. R.; Leurs, Rob; Esch, Iwan J. P. de

doi:10.1021/jm300801u

Cited by 33 publications

(27 citation statements)

References 46 publications

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“…The minimum energy conformation (three least energy conformations for each compound) of each designed molecule was generated by ACDLABS‐10.0/3D Viewer (CHARMM parameterization), and the pharmacophoric distances were measured from centroid of 1,8 naphthyridine ring to oxygen of the carbonyl group, carbonyl oxygen to basic nitrogen atom (N4 of piperazines), and centroid of 1,8 naphthyridine ring to basic nitrogen. The observed distances between the pharmacophoric elements of all the designed compounds are in agreement with the earlier proposed pharmacophore model (Figure ; ) for 5‐HT 3 receptor antagonists. Lipophilicity is an important parameter to be considered while designing compound to manifest drug‐like behavior.…”

Section: Physical Constants Of Synthesized Compounds 8a‐8osupporting

confidence: 90%

“…Thus, synthesis of a series of novel 1,8‐naphthyridine‐3‐carboxamides as 5‐HT 3 receptor antagonists was pursued with an intent to examine the antidepressant activity of these compounds. The proposed pharmacophoric elements (Figure ) that are necessary for 5‐HT 3 receptor antagonistic activity are an aromatic moiety, a basic moiety, and an intervening hydrogen bond acceptor moiety arranged at specific distances . Our earlier studies have indicated that nitrogen containing fused six‐membered aromatic ring (aromatic moiety) may constitute a suitable template in the design of novel 5‐HT 3 receptor antagonists .…”

Section: Physical Constants Of Synthesized Compounds 8a‐8omentioning

confidence: 99%

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Design, Synthesis and Evaluation of Antidepressant Activity of Novel 2‐Methoxy 1, 8 Naphthyridine 3‐Carboxamides as 5‐HT₃ Receptor Antagonists

et al. 2014

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A series of novel 1,8-naphthyridine-3-carboxamides as 5-HT3 receptor antagonists were synthesized with an intention to explore the antidepressant activity of these compounds. The title carboxamides were designed using ligand-based approach keeping in consideration the structural requirement of the pharmacophore of 5-HT3 receptor antagonists. The compounds were synthesized using appropriate synthetic route from the starting material nicotinamide. 5-HT3 receptor antagonism of all the compounds, which was denoted in the form of pA2 value, was determined in longitudinal muscle myenteric plexus preparation from guinea-pig ileum against 5-HT3 agonist, 2-methyl-5-HT. Compound 8g (2-methoxy-1, 8-naphthyridin-3-yl) (2-methoxy phenyl piperazine-1-yl) methanone was identified as the most active compound, which expressed a pA2 value of 7.67. The antidepressant activity of all the compounds was examined in mice model of forced swim test (FST); importantly, none of the compounds was found to cause any significant changes in the locomotor activity of mice at the tested dose levels. In FST, the compounds with considerably higher pA2 value exhibited promising antidepressant-like activity, whereas compounds with lower pA2 value did not show antidepressant-like activity as compared to the control group.

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Section: Physical Constants Of Synthesized Compounds 8a‐8osupporting

confidence: 90%

Section: Physical Constants Of Synthesized Compounds 8a‐8omentioning

confidence: 99%

Design, Synthesis and Evaluation of Antidepressant Activity of Novel 2‐Methoxy 1, 8 Naphthyridine 3‐Carboxamides as 5‐HT₃ Receptor Antagonists

et al. 2014

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“…The effects of m CPBG at 5-HT 3 A receptors have been reported by several groups, and indeed in one study it was changed from an agonist into an antagonist by mutations in the orthosteric binding site (Spang et al ., 2000; Price et al ., 2008; Verheij et al ., 2012). These studies were performed in rodent receptors where m CPBG has a maximal current response similar to that of 5-HT.…”

Section: Discussionmentioning

confidence: 99%

A single channel mutation alters agonist efficacy at 5‐HT₃A and 5‐HT₃AB receptors

Thompson

Lummis

2013

British J Pharmacology

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BACKGROUND AND PURPOSE5-HT3 receptors are composed of 5-HT3A subunits (homomeric receptors), or combinations of 5-HT3A and other 5-HT3 receptor subunits (heteromeric receptors, the best studied of which are 5-HT3AB receptors). Here we explore the effects of partial agonists at 5-HT3A and 5-HT3AB receptors, and the importance of a channel-lining residue in determining the efficacy of activation.EXPERIMENTAL APPROACHWild type and mutant 5-HT3A and 5-HT3AB receptors were expressed in Xenopus oocytes and examined using two-electrode voltage-clamp, or expressed in HEK293 cells and examined using [3H]granisetron binding.KEY RESULTSDopamine, quipazine and VUF10166 were partial agonists at wild type 5-HT3A and 5-HT3AB receptors, with quipazine and VUF10166 causing a long-lived (>20 min) inhibition of subsequent agonist responses. At 5-HT3A receptors, mCPBG was a partial agonist, but was a superagonist at 5-HT3AB receptors, as it produced a response 2.6× greater than that of 5-HT. A T6'S substitution in the 5-HT3A subunit decreased EC50 and increased Rmax of dopamine and quipazine at both homomeric and heteromeric receptors. The greatest changes were seen with VUF10166 at 5-HT3AT6'SB receptors, where it became a full agonist (EC50 = 7 nM) with an EC50 58-fold less than 5-HT (EC50 = 0.4 μM) and no longer caused inhibition of subsequent agonist responses.CONCLUSIONS AND IMPLICATIONSThese results indicate that a mutation in the pore lining domain in both 5-HT3A and 5-HT3AB receptors alters the relative efficacy of a series of agonists, changing some (e.g. quipazine) from apparent antagonists to potent and efficacious agonists.

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“…Homology modeling : Construction of the homomeric 5-HT 3 A receptor binding site model has been previously described 18. Using the same approach, a model of the 5-HT 3 AB receptor binding site was constructed by homology modeling using MOE (version 2010.10, Chemical Computing Group, Montreal).…”

Section: Methodsmentioning

confidence: 99%

Structure–Activity Relationships of Quinoxaline‐Based 5‐HT₃A and 5‐HT₃AB Receptor‐Selective Ligands

Thompson

Verheij²,

Muijlwijk‐Koezen³

et al. 2013

ChemMedChem

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Until recently, discriminating between homomeric 5-HT3A and heteromeric 5-HT3AB receptors was only possible with ligands that bind in the receptor pore. This study describes the first series of ligands that can discriminate between these receptor types at the level of the orthosteric binding site. During a recent fragment screen, 2-chloro-3-(4-methylpiperazin-1-yl)quinoxaline (VUF10166) was identified as a ligand that displays an 83-fold difference in [3H]granisetron binding affinity between 5-HT3A and 5-HT3AB receptors. Fragment hit exploration, initiated from VUF10166 and 3-(4-methylpiperazin-1-yl)quinoxalin-2-ol, resulted in a series of compounds with higher affinity at either 5-HT3A or 5-HT3AB receptors. These ligands reveal that a single atom is sufficient to change the selectivity profile of a compound. At the extremes of the new compounds were 2-amino-3-(4-methylpiperazin-1-yl)quinoxaline, which showed 11-fold selectivity for the 5-HT3A receptor, and 2-(4-methylpiperazin-1-yl)quinoxaline, which showed an 8.3-fold selectivity for the 5-HT3AB receptor. These compounds represent novel molecular tools for studying 5-HT3 receptor subtypes and could help elucidate their physiological roles.

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Design, Synthesis, and Structure–Activity Relationships of Highly Potent 5-HT₃ Receptor Ligands

Cited by 33 publications

References 46 publications

Design, Synthesis and Evaluation of Antidepressant Activity of Novel 2‐Methoxy 1, 8 Naphthyridine 3‐Carboxamides as 5‐HT₃ Receptor Antagonists

Design, Synthesis and Evaluation of Antidepressant Activity of Novel 2‐Methoxy 1, 8 Naphthyridine 3‐Carboxamides as 5‐HT₃ Receptor Antagonists

A single channel mutation alters agonist efficacy at 5‐HT₃A and 5‐HT₃AB receptors

Structure–Activity Relationships of Quinoxaline‐Based 5‐HT₃A and 5‐HT₃AB Receptor‐Selective Ligands

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Design, Synthesis, and Structure–Activity Relationships of Highly Potent 5-HT3 Receptor Ligands

Cited by 33 publications

References 46 publications

Design, Synthesis and Evaluation of Antidepressant Activity of Novel 2‐Methoxy 1, 8 Naphthyridine 3‐Carboxamides as 5‐HT3 Receptor Antagonists

Design, Synthesis and Evaluation of Antidepressant Activity of Novel 2‐Methoxy 1, 8 Naphthyridine 3‐Carboxamides as 5‐HT3 Receptor Antagonists

A single channel mutation alters agonist efficacy at 5‐HT3A and 5‐HT3AB receptors

Structure–Activity Relationships of Quinoxaline‐Based 5‐HT3A and 5‐HT3AB Receptor‐Selective Ligands

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Design, Synthesis, and Structure–Activity Relationships of Highly Potent 5-HT₃ Receptor Ligands

Design, Synthesis and Evaluation of Antidepressant Activity of Novel 2‐Methoxy 1, 8 Naphthyridine 3‐Carboxamides as 5‐HT₃ Receptor Antagonists

Design, Synthesis and Evaluation of Antidepressant Activity of Novel 2‐Methoxy 1, 8 Naphthyridine 3‐Carboxamides as 5‐HT₃ Receptor Antagonists

A single channel mutation alters agonist efficacy at 5‐HT₃A and 5‐HT₃AB receptors

Structure–Activity Relationships of Quinoxaline‐Based 5‐HT₃A and 5‐HT₃AB Receptor‐Selective Ligands