The selectivity in vitro of the stereoisomers of the beta-3 adrenoceptor agonist BRL 37344.
The stimulation by BRL 37344 of lipolysis in rat adipose tissues, and of relaxation of the rat distal colon, is mediated by the beta-3 adrenoceptor. The stereochemical requirements of the beta-3 adrenoceptor are poorly understood. The activities of the four stereoisomers of BRL 37344 (i.e., two pairs of diastereoisomers) on three beta-3 adrenoceptor-mediated responses (brown and white adipose tissue lipolysis and relaxation of distal colon) have been determined and compared with those responses mediated by beta-1 adrenoceptors (increase in atrial rate) and beta-2 adrenoceptors (uterine relaxation). The potency order for the stereoisomers (RR>RS=SR>>SS) was the same for all tissues, regardless of whether the response was mediated by beta-1, beta-2 or beta-3 adrenoceptors. These results indicate that both chiral centers are determinants of agonist potency at all three subtypes of the beta adrenoceptor. Furthermore, agonist activity at beta-1, beta-2 and beta-3 adrenoceptors resides predominantly with the RR enantiomer. Finally, the RR enantiomer of BRL 37344 was a more potent agonist in brown adipocytes (EC50 = 3.3 +/- 0.8 nM) than in white adipocytes (EC50 = 5.7 +/- 0.9 nM) or colon (EC50 = 27.5 +/- 7.7 nM).
Oriowo
M A
MA
Department of Vascular Biology, SmithKline Beecham Pharmaceuticals, Epsom, Surrey, England.
Chapman
H
H
Kirkham
D M
DM
Sennitt
M V
MV
Ruffolo
R R
RR
Cawthorne
M A
MA
D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D004983:Ethanolamines / Q000494:pharmacology*; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D011943:Receptors, Adrenergic, beta / Q000187:drug effects*; D022702:Receptors, Adrenergic, beta-3; D013237:Stereoisomerism; D014590:Uterine Contraction / Q000187:drug effects
D000318:Adrenergic beta-Agonists; D004983:Ethanolamines; D011943:Receptors, Adrenergic, beta; D022702:Receptors, Adrenergic, beta-3; C057368:BRL 37344