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 adren oceptor. The stereochemical requirements of the beta-3 adrenoceptor ar e poorly understood. The activities of the four stereoisomers of BRL 3 7344 (i.e., two pairs of diastereoisomers) on three beta-3 adrenocepto r-mediated responses (brown and white adipose tissue lipolysis and rel axation of distal colon) have been determined and compared with those responses mediated by beta-1 adrenoceptors (increase in atrial rate) a nd beta-2 adrenoceptors (uterine relaxation). The potency order for th e stereoisomers (RR>RS=SR>>SS) was the same for all tissues, regardles s of whether the response was mediated by beta-1, beta-2 or beta-3 adr enoceptors. These results indicate that both chiral centers are determ inants of agonist potency at all three subtypes of the beta adrenocept or. Furthermore, agonist activity at beta-1, beta-2 and beta-3 adrenoc eptors resides predominantly with the RR enantiomer. Finally, the RR e nantiomer of BRL 37344 was a more potent agonist in brown adipocytes ( EC(50) = 3.3 +/- 0.8 nM) than in white adipocytes (EC(50) = 5.7 +/- 0. 9 nM) or colon (EC(50) = 27.5 +/- 7.7 nM).