Binding and functional affinity of some newly synthesized phenethylamine and phenoxypropanolamine derivatives for their agonistic activity at recombinant human β₃-adrenoceptor

β₃-Adrenoceptor is the predominant β-adrenoceptor in adipocytes and has drawn much attention during the investigation for anti-obesity and antidiabetes therapeutics. Thirteen new compounds have been evaluated for their potencies and efficacies as β₃-adrenoceptor agonists on human β₃-adrenoceptor expressed in COS-7 and Chinese hamster ovary (CHO) cells using radioligand binding assay and cyclic AMP (cAMP) accumulation assay. Phenoxypropanolamine derivatives, SWR-0334NA ((E)-[4-[5-[(3-phenoxy-2-hydroxypropyl)amino]-2-pentene-3-yl] phenoxy]acetic acid sodium salt), SWR-0335SA ((E)-[4-[5-[(3-phenoxy-2-hydroxypropyl)amino]-2-pentene-3-yl] phenoxy] acetic acid ethanedioic acid), SWR-0342SA (S-(Z)-[4-[[1-[2-[(2-hydroxy-3-phenoxypropyl)]amino]ethyl]-1-propenyl]phenoxy] acetic acid ethanedioic acid), SWR-0348SA-SITA ((E)-[4-[5-[(3-phenoxy-2-hydroxy-propyl)amino]-2-hexene-3-yl] phenoxy]acetic acid ethanedioic acid) and SWR-0361SA ((E)-N-methyl-[4-[5-[(3-phenoxy-2-hydroxypropyl)amino]-2-pentene-3-yl]phenoxy]ac etoamide ethanedioic acid) showed higher agonistic activity for the β₃-adrenoceptor. Among the compounds tested, SWR-0334NA exhibited full agonist activity (%E_max = 100.26) despite its lower binding affinity (pK₁ = 6.11). Compounds SWR-0338SA ((E)-[4-[5-[(2-phenyl-2-hydroxyethyl)amino]-2-pentene-3-yl] phenoxy]acetic acid ethanedioic acid), SWR-0339SA (S-(E)-[4-[5-[(3-phenoxy-2-hydroxypropyl)amino]-2- pentene-3-yl] phenoxy] acetic acid ethanedioic acid), SWR-0345HA ((E)-2-methyl-3-[4-[2-(2-phenyl-2-hydroxyethyl-amino)ethoxy] phenyl]-2-propenoic acid ethyl ester hydrochloride), SWR-0358SA ((E)-(2-methoxyethyl)-[4-[5-[(3-phenoxy-2-hydroxypropyl) amino]-2-pentene-3-yl]phenoxy]acetoamide ethanedioic acid) and SWR-0362SA ((E)-1-[[[4-[5-[(3-phenoxy-2-hydroxypropyl)amino]-2-pentene -3yl]phenoxy]-acetyl]carbonyl]piperidine ethanedioic acid) had moderate agonistic activity and were phenethylamine and phenoxypropanolamine derivatives. Compounds SWR-0065HA ([4-[2-[3-[[(3,4-dihydro-4-oxo-[1,2,4]-triazino(4,5-a)indol)-lyl]oxy]-2-hydroxyp ropylamino]ethoxy]phenyl]acetic acid methyl ester hydrochloride), SWR-0098NA ((E)-[4-[3-[(2-phenyl-2-hydroxyethyl)amino]-1-butenyl] phenoxy]-acetic acid sodium salt) and SWR-0320HA ([4-[[4-[2-(3-chlorophenoxy-2-hydroxypropyl)amino]-E-2-butenyl]oxy]phenoxy]aceti c acid hydrochloride) had very low binding affinity towards β₃-adrenoceptors and they did not induce cAMP accumulation. We concluded that compounds SWR-0334NA, SWR-0335SA, SWR-0342SA, SWR-0348SA-SITA and SWR-0361SA were potential agonists of human β₃-adrenoceptor. Further investigation on their selectivity towards β₃-adrenoceptor could be useful for the exploration of the physiological properties of the β₃-adrenoceptor.