Affinity of aporphines for the human 5-HT2A receptor: Insights from homology modeling and molecular docking studies

Pecic, Stevan; Makkar, Pooja; Chaudhary, Sandeep; Reddy, Boojala Vijay B.; Navarro, Hernán A.; Harding, Wayne W.

doi:10.1016/j.bmc.2010.06.043

Cited by 33 publications

(32 citation statements)

References 51 publications

(67 reference statements)

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“…22,23,25,30 The 1,2,9,10-tetraoxygenated pattern seems to endow aporphines with a bias for affinity to 5-HT receptors. However, an extensive evaluation of the impact of structural manipulations on the affinity of this scaffold across various 5-HT receptors is in need of attention.…”

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confidence: 95%

Semisynthetic Studies on and Biological Evaluation of N-Methyllaurotetanine Analogues as Ligands for 5-HT Receptors

Madapa

Harding

2015

J. Nat. Prod.

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N-Methyllaurotetanine (1) has been reported to display good affinity for the 5-HT1A receptor, but no structure-affinity studies have been performed to date. The commercially available alkaloid boldine (2) was used as the starting material for synthesis of various C-9 alkoxy analogues of N-methyllaurotetanine in order to gauge the effect of C-9 alkylation on affinity and selectivity at 5-HT1A, 5-HT2A, and 5-HT7 receptors. Mitsunobu reactions were implemented in the alkylation steps leading to the analogues. Modest improvement in 5-HT1A affinity was observed upon alkylation for most analogues. Thus, the C-9 hydroxy group of 1 is not critical for affinity to the 5-HT1A receptor. Some analogues displayed high affinity for the 5-HT7 receptor, comparable to N-methyllaurotetanine, with moderate selectivity vs 5-HT1A and 5-HT2A receptors.

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confidence: 95%

Semisynthetic Studies on and Biological Evaluation of N-Methyllaurotetanine Analogues as Ligands for 5-HT Receptors

Madapa

Harding

2015

J. Nat. Prod.

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“…[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.…”

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confidence: 99%

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

2015

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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 ...

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“…Benzo [d] [1,3]dioxole derivatives have driven much attention for their broad spectrum of biological properties [1] and have been used as 5-HT 2A receptorantagonist [2] and CB1R inverse agonists. In addition, some benzo[d] [1,3]dioxole derivatives are indispensable building blocks in functional materials [3].…”

Section: Discussionmentioning

confidence: 99%

Crystal structure of (E)-ethyl 2-(2-(2-(2,4-dinitrophenyl)hydrazono)-2- phenylethyl)-2,5-dimethyl-7-phenylbenzo[d][1,3]dioxole-4-carboxylate, C32H27N4O8

Wang

Fan

Feng

et al. 2013

Zeitschrift Für Kristallographie - New Crystal Structures

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Source of materialTo a flask containing ethyl 2,and (2,4-dinitrophenyl)hydrazine (1.0 mmol) in ethanol (5 mL) was added anhydrous CaCl 2 (2.0 mmol). The solution was stirred at reflux for 48 h, and then concentrated under vacuum. The residue was purified by column chromatography on silica gel eluenting with ethyl acetate/hexane (v:v = 1:5) to give the title compound as a mixture of E/Z isomers with a total yield of 52% (E:Z = 10:3). Single crystals of title compound were obtained by slow evaporation of its chloroform/petroleum ether solution at room temperature.

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Affinity of aporphines for the human 5-HT2A receptor: Insights from homology modeling and molecular docking studies

Cited by 33 publications

References 51 publications

Semisynthetic Studies on and Biological Evaluation of N-Methyllaurotetanine Analogues as Ligands for 5-HT Receptors

Semisynthetic Studies on and Biological Evaluation of N-Methyllaurotetanine Analogues as Ligands for 5-HT Receptors

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

Crystal structure of (E)-ethyl 2-(2-(2-(2,4-dinitrophenyl)hydrazono)-2- phenylethyl)-2,5-dimethyl-7-phenylbenzo[d][1,3]dioxole-4-carboxylate, C32H27N4O8

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Affinity of aporphines for the human 5-HT2A receptor: Insights from homology modeling and molecular docking studies

Cited by 33 publications

References 51 publications

Semisynthetic Studies on and Biological Evaluation of N-Methyllaurotetanine Analogues as Ligands for 5-HT Receptors

Semisynthetic Studies on and Biological Evaluation of N-Methyllaurotetanine Analogues as Ligands for 5-HT Receptors

Identification of tris-(phenylalkyl)amines as new selective h5-HT2B receptor antagonists

Crystal structure of (E)-ethyl 2-(2-(2-(2,4-dinitrophenyl)hydrazono)-2- phenylethyl)-2,5-dimethyl-7-phenylbenzo[d][1,3]dioxole-4-carboxylate, C32H27N4O8

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