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 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.
Hodson
Stephen J
SJ
GlaxoSmithKline Research and Development, Research Triangle Park, NC 27709, USA.
Bigham
Eric C
EC
Garrison
Deanna T
DT
Gobel
Michael J
MJ
Irving
Paul E
PE
Liacos
James A
JA
Navas
Frank
F
Saussy
David L
DL
Sherman
Bryan W
BW
Speake
Jason D
JD
Bishop
Michael J
MJ
D058646:Adrenergic alpha-1 Receptor Agonists; D000316:Adrenergic alpha-Agonists / Q000737:chemistry* / Q000494:pharmacology*; D000814:Aniline Compounds / Q000737:chemistry*; D006801:Humans; D007093:Imidazoles / Q000737:chemistry* / Q000494:pharmacology*; D010647:Phenyl Ethers / Q000737:chemistry*; D011994:Recombinant Proteins / Q000819:agonists; D013329:Structure-Activity Relationship
D058646:Adrenergic alpha-1 Receptor Agonists; D000316:Adrenergic alpha-Agonists; D000814:Aniline Compounds; D007093:Imidazoles; D010647:Phenyl Ethers; D011994:Recombinant Proteins