The goal of the present study was to modulate the receptor interaction properties of known alpha2-adrenoreceptor (AR) antagonists to obtain novel alpha2-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 alpha2-AR agonists and the significant alpha2C-AR subtype selective activation displayed by 11 and 15 demonstrated that favorable interactions to induce alpha2-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.
alpha(2)-adrenoreceptors profile modulation. 4. From antagonist, to agonist behavior
GENTILI, Francesco;GIANNELLA, Mario;PIERGENTILI, Alessandro;QUAGLIA, Wilma;PIGINI, Maria
2008-01-01
Abstract
The goal of the present study was to modulate the receptor interaction properties of known alpha2-adrenoreceptor (AR) antagonists to obtain novel alpha2-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 alpha2-AR agonists and the significant alpha2C-AR subtype selective activation displayed by 11 and 15 demonstrated that favorable interactions to induce alpha2-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.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
