The selectivity in vitro of the stereoisomers of the beta-3 adrenoceptor agonist BRL 37344
Oriowo, M.A.; Chapman, H.; Kirkham, D.M.; Sennitt, M.V.; Ruffolo, R.R.; Cawthorne, M.A.
Journal of Pharmacology and Experimental Therapeutics 277(1): 22-27
1996
ISSN/ISBN: 0022-3565 PMID: 8613923 Document Number: 463708
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).