IngentaConnect Comparison of the binding affinity of some newly synthesized phen...

Abstract:

We evaluated six new 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 ((R*R*-UE)-(E)-[4-[3-[(2-phenyl-2-hydroxyethyl)amino]-1-butenyl]phenoxy]acetic acid sodium salt), SWR-0315NA ((E, Z)-[4[[1-[2-[(3-phenoxy-2-hydroxy propyl)]amino]ethyl]-1-propenyl]phenoxy]acetic acid sodium), SWR-0338SA ((E)-[4-[5-[(2-phenyl-2-hydroxyethyl)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) and SWR-0345HA ((E)-2-methyl-3-[4-[2-(2-phenyl-2-hydroxyethylamino)ethoxy]phenyl]-2-propenoic acid ethyl ester hydrochloride) for their potencies as selective ligands at human -adrenoceptors expressed in COS-7 cells and compared the binding affinities for human ₁-adrenoceptors expressed in Chinese hamster ovary (CHO) cells using a radioligand-binding assay. Phenoxypropanolamine derivatives SWR-0315NA and SWR-0342SA showed higher binding affinities for -adrenoceptor subtypes; SWR-0065HA, however, showed a higher affinity for only -adrenoceptors, accounting for 3-fold and 6-fold selectivity against ₁- and ₃-adrenoceptors. Compounds SWR-0315NA and SWR-0342SA did not show any binding selectivity for any of the subtypes. However, functionally these two compounds are selective for ₃-adrenoceptors. Among the phenylethanolamine derivatives, SWR-0338SA and SWR-0345HA showed 9-fold and 16-fold higher binding selectivity for ₃-adrenoceptors against ₁-adrenoceptors, respectively, whereas they both showed a 7-fold higher binding selectivity for ₃-adrenoceptors against ₂-adrenoceptors. SWR-0098NA did not show any significant binding affinity for any of the -adrenoceptor subtypes. These compounds, except for SWR-0098NA, were not found to possess any significant binding affinity for ₁-adrenoceptor subtypes over that for -adrenoceptor subtypes. However, SWR-0098NA has about a 3-fold to 22-fold higher binding selectivity for ₁-adrenoceptor subtypes against -adrenoceptor subtypes, making it difficult for use in a -adrenoceptor receptor study. Compounds SWR-0315NA and SWR-0342SA have similar binding potency for ₁-adrenoceptors as adrenaline (epinephrine), proving the finding of this manuscript that this phenoxypropanolamine group of -adrenoceptor ligands could also be used as ₁-adrenoceptor ligands. Functional assays have to be performed to confirm their agonistic activity.

Document Type: Research article

DOI: 10.1211/0022357055074

Affiliations: 1: Department of Pharmacology, Niigata University of Pharmacy and Applied Life Sciences, 5-13-2 Kamishinei-cho, Niigata 950-2081, Japan 2: Research Department, Sawai Pharmaceutical Co. Ltd., 1-8-14 Ikue, Asahi-ku, Osaka 535-0004, Japan 3: Department of Pharmacology, School of Medicine, Fukui Medical University, 23 Shimoaizuki, Matsuoka, Fukui 910-1193, Japan

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Comparison of the binding affinity of some newly synthesized phenylethanolamine and phenoxypropanolamine compounds at recombinant human - and 1-adrenoceptor subtypes

Comparison of the binding affinity of some newly synthesized phenylethanolamine and phenoxypropanolamine compounds at recombinant human - and ₁-adrenoceptor subtypes