Alpha(1)-adrenoceptor activation: a comparison of 4-(anilinomethyl)imidazoles and 4-(phenoxymethyl)imidazoles to related 2-imidazolines

Literature reports suggest that disruption of an interhelical salt bridge is critical for alpha(1)-adrenoceptor activation, and the basic amine found in adrenergic receptor ligands is responsible for the disruption. Novel 4-(anilinomethyl)imidazoles and 4-(phenoxymethyl)imidazoles are agonists of th...

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Published in:Bioorganic & medicinal chemistry letters 2002-12, Vol.12 (23), p.3449-3452
Main Authors: Hodson, Stephen J, Bigham, Eric C, Garrison, Deanna T, Gobel, Michael J, Irving, Paul E, Liacos, James A, Navas, 3rd, Frank, Saussy, Jr, David L, Sherman, Bryan W, Speake, Jason D, Bishop, Michael J
Format: Article
Language:English
Subjects:
Adrenergic alpha-1 Receptor Agonists
Adrenergic alpha-Agonists - chemistry
Adrenergic alpha-Agonists - pharmacology
Aniline Compounds - chemistry
Humans
Imidazoles - chemistry
Imidazoles - pharmacology
Phenyl Ethers - chemistry
Recombinant Proteins - agonists
Structure-Activity Relationship
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Summary:Literature reports suggest that disruption of an interhelical salt bridge is critical for alpha(1)-adrenoceptor activation, and the basic amine found in adrenergic receptor ligands is responsible for the disruption. Novel 4-(anilinomethyl)imidazoles and 4-(phenoxymethyl)imidazoles are agonists of the cloned human alpha(1)-adrenoceptors in vitro, and potent, selective alpha(1A)-adrenoceptor agonists have been identified in this series. These imidazoles demonstrate similar potencies and alpha(1)-subtype selectivities as the corresponding 2-substituted imidazolines. The extremely close SAR suggests that, in spite of the large difference in basicity, these imidazoles and imidazolines may establish the same interactions to activate alpha(1)-adrenoceptors.
ISSN:0960-894X
DOI:10.1016/S0960-894X(02)00753-9