Two stereoisomeric imidazoline derivatives: synthesis and optical and alpha 2-adrenoceptor activities.
Two eight-step pathways for synthesizing the stereoisomeric compounds (-)-2-[1-(2,6-dichlorophenoxy)ethyl]-2-imidazoline hydrochloride ("levlofexidine" hydrochloride; (-)-lofexidine hydrochloride) and (+)-2-[1-(2,6-dichlorophenoxy)ethyl]-2-imidazoline hydrochloride ("dexlofexidine" hydrochloride; (+)-lofexidine hydrochloride) and the optical resolution of (+/-)-lofexidine are described. (-)-Lofexidine, a stereoselective alpha 2-adrenoceptor agonist, due to its center of asymmetry, is demonstrated to be a potent drug for the treatment of hypertension (doses 0.561 microgram/kg) and to have the highest affinity and a concentration dependency for alpha 2-adrenoceptors in direct binding studies (0.36 nmol/L). (+)-Lofexidine is 10 times less potent.
D000316:Adrenergic alpha-Agonists / Q000138:chemical synthesis*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D001921:Brain / Q000378:metabolism; D003000:Clonidine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical; D007093:Imidazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D007202:Indicators and Reagents; D008297:Male; D009904:Optical Rotation; D051381:Rats; D011919:Rats, Inbred Strains; D011942:Receptors, Adrenergic, alpha / Q000187:drug effects / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D000316:Adrenergic alpha-Agonists; D007093:Imidazoles; D007202:Indicators and Reagents; D011942:Receptors, Adrenergic, alpha; D003000:Clonidine; C025655:lofexidine