Alpha2-adrenoreceptors profile modulation. 4. From antagonist to agonist behavior.

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Gentili F, Cardinaletti C, Vesprini C, Carrieri A, Ghelfi F, Farande A, Giannella M, Piergentili A, Quaglia W, Laurila JM, Huhtinen A, Scheinin M, Pigini M

Alpha2-adrenoreceptors profile modulation. 4. From antagonist to agonist behavior.

J Med Chem. 2008 Jul 24;51(14):4289-99. doi: 10.1021/jm800250z. Epub 2008 Jun 25.

PubMed ID

18578476 [ View in PubMed

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Abstract

The goal of the present study was to modulate the receptor interaction properties of known alpha 2-adrenoreceptor (AR) antagonists to obtain novel alpha 2-AR agonists with desirable subtype selectivity. Therefore, a phenyl group or one of its bioisosteres or aliphatic moieties with similar steric hindrance were introduced into the aromatic ring of the antagonist lead basic structure. The functional properties of the novel compounds allowed our previous observations to be confirmed. The high efficacy of 7, 12, and 13 as alpha 2-AR agonists and the significant alpha 2C-AR subtype selective activation displayed by 11 and 15 demonstrated that favorable interactions to induce alpha 2-AR activation were formed between the pendant groups of the ligands and the aromatic cluster present in transmembrane domain 6 of the binding site cavity of the receptors.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Norepinephrine	Alpha-2A adrenergic receptor	EC 50 (nM)	371.54	N/A	N/A	Details
Norepinephrine	Alpha-2B adrenergic receptor	EC 50 (nM)	61.66	N/A	N/A	Details
Norepinephrine	Alpha-2C adrenergic receptor	EC 50 (nM)	794.33	N/A	N/A	Details