2-(Anilinomethyl)imidazolines as alpha1 adrenergic receptor agonists: the discovery of alpha1a subtype selective 2'-alkylsulfonyl-substituted analogues.
A series of 2'-alkylthio-2-(anilinomethyl)imidazolines were prepared to examine the effect of the alkyl group size, sulfur oxidation state, and phenyl ring substitution on ligand binding and agonism of alpha-adrenergic receptor subtypes alpha1a, alpha1b, alpha1d, alpha2a, and alpha2c. Binding at all receptor subtypes decreased for compounds in the sulfone oxidation state as compared to their sulfide analogues. While sulfides were generally potent, nonselective agonists, sulfones exhibited alpha1a subtype selectivity in a cell-based functional assay. Sulfone (32) was 250-7000-fold selective for alpha1a vs all other subtypes.
Hodson
Stephen J
SJ
GlaxoSmithKline Research Laboratories, P.O. Box 13398, Research Triangle Park, North Carolina 27709-3398, USA.
Bishop
Michael J
MJ
Speake
Jason D
JD
Navas
Frank
F
Garrison
Deanna T
DT
Bigham
Eric C
EC
Saussy
David L
DL
Liacos
James A
JA
Irving
Paul E
PE
Gobel
M Jeffrey
MJ
Sherman
Bryan W
BW
D000316:Adrenergic alpha-Agonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D000242:Cyclic AMP / Q000096:biosynthesis; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018340:Receptors, Adrenergic, alpha-1 / Q000187:drug effects*; D013450:Sulfones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
C455802:2'-methylsulfonyl-5'-methoxy-2-(anilinomethyl)imidazoline; C547713:ADRA1A protein, human; D000316:Adrenergic alpha-Agonists; D007093:Imidazoles; D018340:Receptors, Adrenergic, alpha-1; D013450:Sulfones; D000242:Cyclic AMP; D002118:Calcium