Alpha(2) adrenoceptor agonists as potential analgesic agents. 3. Imidazolylmethylthiophenes.
A series of imidazolylmethylthiophenes has been prepared and evaluated as ligands for the alpha(2) adrenoceptor. These compounds were tested in two animal models that are predictive of analgesic activity in humans. The 3-thienyl compounds were generally the most potent, particularly those with substitution in the 4-position. A subset of the most active compounds was further evaluated for adverse cardiovascular effects in the anesthetized rat model. In addition to excellent binding at the alpha(2D) adrenoceptor, the 4-bromo analogues 20e and 21e were very active in the rat abdominal irritant test (RAIT) with ED(50) doses of 0.38 and 0.31 mg/kg, respectively. We constructed a pharmacophore model based on the biological activity of the present series, dexmedetomidine (1), and conformationally restrained analogues 3 and 4.
Boyd
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RE
Drug Discovery Division, The R. W. Johnson Pharmaceutical Research Institute, Welsh and McKean Roads, Spring House, Pennsylvania 19477, USA. rboyd@prius.jnj.com
Press
J B
JB
Rasmussen
C R
CR
Raffa
R B
RB
Codd
E E
EE
Connelly
C D
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Li
Q S
QS
Martinez
R P
RP
Lewis
M A
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Almond
H R
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Reitz
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D000316:Adrenergic alpha-Agonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000700:Analgesics / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001921:Brain / Q000378:metabolism; D004562:Electrocardiography; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008958:Models, Molecular; D051381:Rats; D020318:Rats, Long-Evans; D017208:Rats, Wistar; D018341:Receptors, Adrenergic, alpha-2 / Q000187:drug effects* / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
C424430:4-((4-bromothiophen-3-yl)ethyl)-1H-imidazole; D000316:Adrenergic alpha-Agonists; D000700:Analgesics; D007093:Imidazoles; D018341:Receptors, Adrenergic, alpha-2; D013876:Thiophenes