Medetomidine analogs as alpha 2-adrenergic ligands. 2. Design, synthesis, and biological activity of conformationally restricted naphthalene derivatives of medetomidine.
A new series of naphthalene analogs of medetomidine have been prepared and evaluated for their alpha-adrenergic activities. The methylnaphthyl analog 5a showed significant selectivity for alpha 2-adrenoceptors and behaved as a partial alpha 1-agonist in rat aorta preparations. In contrast, the Z-ethylene analog 8c was alpha 1-selective and behaved as a potent alpha 1-antagonist. Two rigid analogs (6 and 7) exhibited large differences in binding affinities at alpha 1-VS alpha 2-receptors, indicating that the conformational flexibility of 5a is important for the fulfillment of the alpha-adrenergic activities. Molecular modeling studies began with conformational analysis of classical phenethylamines and medetomidine analogs. Superimposition of medetomidine conformations with those of phenethylamines provided a tentative explanation for the alpha 2-adrenergic activity of the new imidazoles. A common binding mode for phenethylamines and imidazoles with alpha 2-adrenoceptors is proposed. Knowledge of the biological properties of the 4-substituted imidazoles, integrated with the information derived from computer-assisted molecular modeling, has provided new insights for the structural and conformational requirements of this class as new adrenergic drugs.
Zhang
X
X
Division of Medicinal Chemistry & Pharmacology, College of Pharmacy, Ohio State University, Columbus 43210, USA.
Yao
X T
XT
Dalton
J T
JT
Shams
G
G
Lei
L
L
Patil
P N
PN
Feller
D R
DR
Hsu
F L
FL
George
C
C
Miller
D D
DD
D000316:Adrenergic alpha-Agonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001011:Aorta / Q000502:physiology; D002462:Cell Membrane / Q000378:metabolism; D002540:Cerebral Cortex / Q000378:metabolism; D018360:Crystallography, X-Ray; D015195:Drug Design; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000737:chemistry*; D008297:Male; D020926:Medetomidine; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D009119:Muscle Contraction / Q000187:drug effects; D009281:Naphthalenes / Q000737:chemistry*; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D051381:Rats; D011942:Receptors, Adrenergic, alpha / Q000187:drug effects / Q000378:metabolism; D013329:Structure-Activity Relationship
D000316:Adrenergic alpha-Agonists; D007093:Imidazoles; D009281:Naphthalenes; D010975:Platelet Aggregation Inhibitors; D011942:Receptors, Adrenergic, alpha; C031721:naphthalene; D020926:Medetomidine