New aporphinoid 5-HT2A and α1A antagonists via structural manipulations of nantenine

Chaudhary, Sandeep; Ponnala, Shashikanth; LeGendre, Onica; Gonzales, Junior; Navarro, Hernán A.; Harding, Wayne W.

doi:10.1016/j.bmc.2011.08.019

Cited by 21 publications

(25 citation statements)

References 31 publications

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“…22,25 Thus, it was of interest to determine if a similar alkylation strategy would be beneficial for 5-HT 1A affinity in the case of N-methyllaurotetanine at the C-9 position.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

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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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“…22,25 Thus, it was of interest to determine if a similar alkylation strategy would be beneficial for 5-HT 1A affinity in the case of N-methyllaurotetanine at the C-9 position.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

“…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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“…25–27 A similar set of assays was performed for the α 1A - adrenergic receptor. Data from these evaluations are presented in Table 1.…”

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Evaluation of structural effects on 5-HT2A receptor antagonism by aporphines: Identification of a new aporphine with 5-HT2A antagonist activity

Ponnala

Gonzales

Kapadia

et al. 2014

Bioorganic & Medicinal Chemistry Letters

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A set of aporphine analogs related to nantenine was evaluated for antagonist activity at 5-HT2A and α1A adrenergic receptors. With regards to 5-HT2A receptor antagonism, a C2 allyl group is detrimental to activity. The chiral center of nantenine is not important for 5-HT2A antagonist activity, however the N6 nitrogen atom is a critical feature for 5-HT2A antagonism. Compound 12b was the most potent 5-HT2A aporphine antagonist identified in this study and has similar potency to previously identified aporphine antagonists 2 and 3. The ring A and N6 modifications examined were detrimental to α1A antagonism. A slight eutomeric preference for the R enantiomer of nantenine was observed in relation to α1A antagonism.

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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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New aporphinoid 5-HT2A and α1A antagonists via structural manipulations of nantenine

Cited by 21 publications

References 31 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

Evaluation of structural effects on 5-HT2A receptor antagonism by aporphines: Identification of a new aporphine with 5-HT2A antagonist activity

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

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New aporphinoid 5-HT2A and α1A antagonists via structural manipulations of nantenine

Cited by 21 publications

References 31 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

Evaluation of structural effects on 5-HT2A receptor antagonism by aporphines: Identification of a new aporphine with 5-HT2A antagonist activity

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

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