Development of high-affinity 5-HT3 receptor antagonists. 1. Initial structure-activity relationship of novel benzamides

Youssefyeh, R. D.; Campbell, H. F.; Klein, Scott I.; Airey, J. E.; Darkes, P.; Powers, Mike D.; Schnapper, M.; Neuenschwander, Kent; Fitzpatrick, Leo R.

doi:10.1021/jm00083a014

Cited by 21 publications

(5 citation statements)

References 2 publications

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“…TLC R f = 0.30 (20% EtOAc in n -heptane, v/v); 1 H NMR (400 MHz, CDCl 3 ): δ 7.23–7.16 (m, 1H), 7.15–7.11 (m, 1H), 7.11–7.05 (m, 1H), 6.99 (dd, J = 1.0, 8.0 Hz, 1H), 2.74 (t, J = 7.5 Hz, 2H), 2.38 (t, J = 7.0 Hz, 2H), 2.10 (pen, J = 7.0 Hz, 2H); 13 C NMR (101 MHz, CDCl 3 ): δ 171.4, 151.8, 130.0, 129.7, 128.3, 125.9, 119.2, 31.0, 28.2, 26.5. The data are agreement with that reported by others …”

Section: Methodssupporting

confidence: 93%

Probing the Existence of a Metastable Binding Site at the β₂-Adrenergic Receptor with Homobivalent Bitopic Ligands

et al. 2019

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Herein, we report the development of bitopic ligands aimed at targeting the orthosteric binding site (OBS) and a metastable binding site (MBS) within the same receptor unit. Previous molecular dynamics studies on ligand binding to the β2-adrenergic receptor (β2AR) suggested that ligands pause at transient, less-conserved MBSs. We envisioned that MBSs can be regarded as allosteric binding sites and targeted by homobivalent bitopic ligands linking two identical pharmacophores. Such ligands were designed based on docking of the antagonist (S)-alprenolol into the OBS and an MBS and synthesized. Pharmacological characterization revealed ligands with similar potency and affinity, slightly increased β2/β1AR-selectivity, and/or substantially slower β2AR off-rates compared to (S)-alprenolol. Truncated bitopic ligands suggested the major contribution of the metastable pharmacophore to be a hydrophobic interaction with the β2AR, while the linkers alone decreased the potency of the orthosteric fragment. Altogether, the study underlines the potential of targeting MBSs for improving the pharmacological profiles of ligands.

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Section: Methodssupporting

confidence: 93%

Probing the Existence of a Metastable Binding Site at the β₂-Adrenergic Receptor with Homobivalent Bitopic Ligands

et al. 2019

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“…Compounds with only one hydrophobic substituent on the phenyl ring in a meta position from the imidazole and quinuclidine series have a greater potency than the corresponding unsubstituted structures (compare 21 and 29 ; 56 and 59 ). The same pattern of activity has been reported for 5-HT 3 receptor antagonists, belonging to other chemical series. , However, among the compounds we prepared, the meta-substituted molecules have a potency lower than that of the corresponding double-meta-substituted ones ( 28, 58 , and 63 ) . In our model, the chloro atom of the para-substituted inactive compounds 25 and 64 occupies the space located between the two hydrophobic sites (Figure ).…”

Section: Molecular Modelingsupporting

confidence: 79%

“…The same pattern of activity has been reported for 5-HT 3 receptor antagonists, belonging to other chemical series. 30,31 However, among compounds we prepared, the meta-substituted molecules have a potency lower than that of the corre- a None of the compounds showed affinity for D1, D2, R1, R2, M1+2, 5-HT1, 5-HT1A, 5-HT2, and 5-HT4 receptor binding sites (IC50 >10 µM), or agonistic (EC50 >1 µM) or antagonistic activity (Kb > 1 µM) on rat oesophagus preparation (5-HT4 receptor). sponding double-meta-substituted ones (28, 58, and 63).…”

Section: Molecular Modelingmentioning

confidence: 99%

Phenylimidazolidin-2-one Derivatives as Selective 5-HT₃Receptor Antagonists and Refinement of the Pharmacophore Model for 5-HT₃Receptor Binding

Heidempergher¹,

Pillan²,

Pinciroli³

et al. 1997

J. Med. Chem.

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A possible bioisosterism between the benzamido and the phenylimidazolidin-2-one moieties has been suggested on the basis of the similarity between the molecular electrostatic potential (MEP) of metoclopramide, a D2 receptor antagonist with weak 5-HT3 receptor antagonist properties, and zetidoline, a D2 receptor antagonist. Starting from this premise, a series of phenylimidazolidin-2-one derivatives bearing a basic azabicycloalkyl or an imidazolylalkyl moiety were synthesized and evaluated for 5-HT3 receptor radioligand binding affinity ([3H]-GR 43,694). In vitro 5-HT3 receptor antagonist activity was tested in the guinea pig ileum assay (GPI). A number of high-affinity ligands were shown to be potent 5-HT3 receptor antagonists in vivo as determined by inhibition of the Bezold--Jarisch reflex in the anesthetized rat. In general, the imidazolylalkyl derivatives were found to be more active than azabicycloalkyls. 1-(3,5-Dichlorophenyl)-3-[(5-methyl-1H-imidazol-4-yl)methyl]imidazoli din-2-one (58), in particular, displayed very high affinity for the 5-HT3 receptor (Ki of 0.038 nM) with a Kb of 5.62 nM in the GPI assay, being more potent than the reference compounds (ondansetron, tropisetron, granisetron, and BRL 46,470) tested. 58 showed an ID50 comparable to that of ondansetron (2.2 micrograms/kg i.v.) in the Bezold--Jarisch reflex. A molecular modeling study based on this structurally novel series of compounds allowed the refinement of previously reported 5-HT3 receptor antagonist pharmacophore models.

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“…Catalytic reduction of the 5-nitro derivative 7 provided the 5-amino analog 9. The 5-hydroxy derivative 10 was obtained by deprotection of the 5-benzyloxy analog 8. The secondary amides [17][18][19][20][21] resulted from the reaction of the imidazolide of 3 with primary amines (Scheme 1).…”

Section: Chemistrymentioning

confidence: 99%

Inhibition of E-Selectin-, ICAM-1-, and VCAM-1-Mediated Cell Adhesion by Benzo[b]thiophene-, Benzofuran-, Indole-, and Naphthalene-2-carboxamides: Identification of PD 144795 as an Antiinflammatory Agent

Dh¹,

Jb²,

Ss³

et al. 1995

J. Med. Chem.

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It was previously reported that 3-alkoxybenzo[b]thiophene-2-carboxamides exemplified by 1, 5-methoxy-3-(1-methylethoxy)benzo[b]thiophene-2-carboxamide, decreased the adherence of neutrophils to activated endothelial cells by inhibiting the upregulation of the adhesion molecules E-selectin and ICAM-1 on the surface of the endothelium. This finding is extended here to a series of 3-thiobenzo[b]thiophene-2-carboxamides and also heterocyclic analogs of 1, including benzofurans, indoles, and napthalenes. The compounds that inhibited the expression of E-selectin and ICAM-1 had the same effect on the expression of VCAM-1. PD 144795, 5-methoxy-3-(1-methylethoxy)benzo[b]thiophene-2-carboxamide 1-oxide (44), the sulfoxide analog of 1, was orally active in several models of inflammation. The in vitro and in vivo activity of PD 144795 resided predominately in the S-enantiomer.

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Development of high-affinity 5-HT3 receptor antagonists. 1. Initial structure-activity relationship of novel benzamides

Cited by 21 publications

References 2 publications

Probing the Existence of a Metastable Binding Site at the β₂-Adrenergic Receptor with Homobivalent Bitopic Ligands

Probing the Existence of a Metastable Binding Site at the β₂-Adrenergic Receptor with Homobivalent Bitopic Ligands

Phenylimidazolidin-2-one Derivatives as Selective 5-HT₃Receptor Antagonists and Refinement of the Pharmacophore Model for 5-HT₃Receptor Binding

Inhibition of E-Selectin-, ICAM-1-, and VCAM-1-Mediated Cell Adhesion by Benzo[b]thiophene-, Benzofuran-, Indole-, and Naphthalene-2-carboxamides: Identification of PD 144795 as an Antiinflammatory Agent

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Development of high-affinity 5-HT3 receptor antagonists. 1. Initial structure-activity relationship of novel benzamides

Cited by 21 publications

References 2 publications

Probing the Existence of a Metastable Binding Site at the β2-Adrenergic Receptor with Homobivalent Bitopic Ligands

Probing the Existence of a Metastable Binding Site at the β2-Adrenergic Receptor with Homobivalent Bitopic Ligands

Phenylimidazolidin-2-one Derivatives as Selective 5-HT3Receptor Antagonists and Refinement of the Pharmacophore Model for 5-HT3Receptor Binding

Inhibition of E-Selectin-, ICAM-1-, and VCAM-1-Mediated Cell Adhesion by Benzo[b]thiophene-, Benzofuran-, Indole-, and Naphthalene-2-carboxamides: Identification of PD 144795 as an Antiinflammatory Agent

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Probing the Existence of a Metastable Binding Site at the β₂-Adrenergic Receptor with Homobivalent Bitopic Ligands

Probing the Existence of a Metastable Binding Site at the β₂-Adrenergic Receptor with Homobivalent Bitopic Ligands

Phenylimidazolidin-2-one Derivatives as Selective 5-HT₃Receptor Antagonists and Refinement of the Pharmacophore Model for 5-HT₃Receptor Binding