In vitro study of a novel atypical beta-adrenoceptor agonist, SM-11044.
SM-11044 (L-threo-3-(3,4-dihydroxyphenyl)-N-[3-(4-fluorophenyl) propyl] serine pyrrolidine amide hydrobromide) stimulated the relaxation of guinea pig ileum (EC50: 3.0 x 10(-8) M), trachea (EC50: 1.3 x 10(-7) M), lung parenchyma (EC50: 2.1 x 10(-6) M) and the increase in right atrial rate (EC50: 6.9 x 10(-6) M). It also induced lipolysis of rat white adipocytes (EC50: 1.2 x 10(-6) M). Both the relaxant response of ileum and the lipolytic response of adipocytes to SM-11044 were resistant to inhibition by propranolol (10(-6) M), but were antagonized by cyanopindolol (10(-6) M). In contrast, the responses to SM-11044 in trachea, lung parenchyma and right atrium were almost completely abolished by propranolol (10(-6) M). Furthermore, the selectivity of SM-11044 relative to isoproterenol was ileum greater than adipocytes greater than trachea (beta 2) greater than lung (beta 2) greater than atrium (beta 1). These results suggest that SM-11044 is a selective agonist of atypical beta-adrenoceptors that are resistant to antagonism by propranolol but sensitive to cyanopindolol. The receptor binding and adenylate cyclase stimulating activity of SM-11044 were also examined on transfected Chinese hamster ovary cells expressing human beta 1-, beta 2- or beta 3-adrenoceptors. SM-11044 inhibited the binding of [125I]iodocyanopindolol to the three types of receptors in a concentration-dependent manner. The selectivity in terms of Ki values was beta 3 (Ki: 1.3 x 10(-6) M) greater than beta 2 (Ki: 4.1 x 10(-6) M) greater than beta 1 (Ki: 18.1 x 10(-6) M)-adrenoceptors.(ABSTRACT TRUNCATED AT 250 WORDS)
Sugasawa
T
T
Research Laboratory, Sumitomo Pharmaceuticals Co., Ltd., Osaka, Japan.
Matsuzaki
M
M
Morooka
S
S
Foignant
N
N
Blin
N
N
Strosberg
A D
AD
D000262:Adenylyl Cyclases / Q000378:metabolism; D000273:Adipose Tissue / Q000166:cytology / Q000187:drug effects; D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000818:Animals; D016466:CHO Cells; D002396:Catechols / Q000494:pharmacology*; D006224:Cricetinae; D004789:Enzyme Activation / Q000187:drug effects; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects; D008066:Lipolysis / Q000187:drug effects; D008168:Lung / Q000187:drug effects; D008297:Male; D009126:Muscle Relaxation / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D012694:Serine / Q000031:analogs & derivatives* / Q000494:pharmacology; D014132:Trachea / Q000187:drug effects
D000318:Adrenergic beta-Agonists; D002396:Catechols; C076952:SM 11044; D012694:Serine; D000262:Adenylyl Cyclases