Alpha2-adrenoreceptors profile modulation. 4. From antagonist to agonist behavior.
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.
Gentili
Francesco
F
Dipartimento di Scienze Chimiche, Università degli Studi di Camerino, via S. Agostino 1, 62032 Camerino, Italy.
Cardinaletti
Claudia
C
Vesprini
Cristian
C
Carrieri
Antonio
A
Ghelfi
Francesca
F
Farande
Aniket
A
Giannella
Mario
M
Piergentili
Alessandro
A
Quaglia
Wilma
W
Laurila
Jonne M
JM
Huhtinen
Anna
A
Scheinin
Mika
M
Pigini
Maria
M
D058647:Adrenergic alpha-2 Receptor Agonists; D058669:Adrenergic alpha-2 Receptor Antagonists; D000316:Adrenergic alpha-Agonists / Q000494:pharmacology*; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology*; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D051381:Rats; D018341:Receptors, Adrenergic, alpha-2 / Q000145:classification
D058647:Adrenergic alpha-2 Receptor Agonists; D058669:Adrenergic alpha-2 Receptor Antagonists; D000316:Adrenergic alpha-Agonists; D000317:Adrenergic alpha-Antagonists; D018341:Receptors, Adrenergic, alpha-2