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

Abstract

Beta(3)-adrenoceptor is the predominant beta-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 beta(3)-adrenoceptor agonists on human beta(3)-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-hydroxypropyl)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]acetoamide ethanedioic acid) showed higher agonistic activity for the beta(3)-adrenoceptor. Among the compounds tested, SWR0334NA exhibited full agonist activity (%E(max) = 100.26) despite its lower binding affinity (pK(I) = 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-3-yl]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-hydroxypropylamino]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-0302HA ([4-[[4-[2-(3-chlorophenoxy-2-hydroxypropyl)amino]-E-2-butenyl]oxy]phenoxy]acetic acid hydrochloride) had very low binding affinity towards beta(3)-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 beta(3)-adrenoceptor. Further investigation on their selectivity towards beta(3)-adrenoceptor could be useful for the exploration of the physiological properties of the beta(3)-adrenoceptor.

Comparison of the binding affinity of some newly synthesized phenylethanolamine and phenoxypropanolamine compounds at recombinant human β- and α1-adrenoceptor subtypes

“…SWR-0345HA also showed high binding selectivity (about 15-fold and 7-fold) for 3 -adrenoceptors against 1 -and 2adrenoceptors. Moreover, SWR-0338SA and SWR-0345HA have high functional efficacy as assessed by cAMP accumulation assay in the cultured CHO cells expressing recombinant human 3 -adrenoceptors (Ahmed et al 2003). Relative to (À)-isoproterenol, SWR-0338SA and SWR-0345HA have respective %E max values of 76.95% and 83.47% for cAMP accumulation in 3 -adrenoceptor CHO cells.…”

“…Some newly synthesized 3 -adrenoceptor agonists, such as SWR-0065HA, SWR-0098NA, SWR-0315NA, SWR-0338SA, SWR-0342SA and SWR-0345HA, have been investigated for their affinity for -adrenoceptor subtypes and 1 -adrenoceptor subtypes by radioligand-binding assay. Affinities of these SWR-compounds for 3 -adrenoceptor subtype have been discussed in our previous article (Ahmed et al 2003). SWR-0315NA has also been proved to be a 3adrenoceptor subtype selective drug in a second messenger accumulation assay (Ahmed et al 2004).…”

Zur Funktion des β3-Adrenozeptors am Herzen: Signaltransduktion, inotroper Effekt und therapeutischer Ausblick

“…So konnte für eine Vielzahl von zurzeit experimentell gebräuchlichen synthetischen β 3 -Agonisten gezeigt werden dass sie neben ihrer β 3 -adrenergen Wirkung auch ausgeprägte positiv inotrope Effekte über β 1/2 -Adrenorezeptoren vermitteln [5,12,20,35,57]. Derzeit werden jedoch neue synthetische β 3 -Adrenozeptoragonisten und -antagonisten entwickelt und auf ihre Spezifität getestet [58][59][60][61][62], so dass in Zukunft die gezieltere pharmakologische Stimulation oder Hemmung des kardialen β 3 -Adrenozeptors möglich sein könnte.…”