title: Comparison of the binding affinity of some newly synthesized phenylethanolamine and phenoxypropanolamine compounds at recombinant human beta- and alpha1-adrenoceptor subtypes.
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 beta-adrenoceptors expressed in COS-7 cells and compared the binding affinities for human alpha(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 beta-adrenoceptor subtypes; SWR-0065HA, however, showed a higher affinity for only beta-adrenoceptors, accounting for 3-fold and 6-fold selectivity against beta(1)- and beta(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 beta(3)-adrenoceptors. Among the phenylethanolamine derivatives, SWR-0338SA and SWR-0345HA showed 9-fold and 16-fold higher binding selectivity for beta(3)-adrenoceptors against beta(1)-adrenoceptors, respectively, whereas they both showed a 7-fold higher binding selectivity for beta(3)-adrenoceptors against beta(2)-adrenoceptors. SWR-0098NA did not show any significant binding affinity for any of the beta-adrenoceptor subtypes. These compounds, except for SWR-0098NA, were not found to possess any significant binding affinity for alpha(1)-adrenoceptor subtypes over that for beta-adrenoceptor subtypes. However, SWR-0098NA has about a 3-fold to 22-fold higher binding selectivity for alpha(1)-adrenoceptor subtypes against beta-adrenoceptor subtypes, making it difficult for use in a beta-adrenoceptor receptor study. Compounds SWR-0315NA and SWR-0342SA have similar binding potency for alpha(1)-adrenoceptors as adrenaline (epinephrine), proving the finding of this manuscript that this phenoxypropanolamine group of beta-adrenoceptor ligands could also be used as alpha(1)-adrenoceptor ligands. Functional assays have to be performed to confirm their agonistic activity.
authors.affiliation: Department of Pharmacology, Niigata University of Pharmacy and Applied Life Sciences, 5-13-2 Kamishinei-cho, Niigata 950-2081, Japan.
authors.forename: Maruf
authors.initials: M
authors.lastname: Ahmed
authors.forename: Yoko
authors.initials: Y
authors.lastname: Hanaoka
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Kiso
authors.forename: Takao
authors.initials: T
authors.lastname: Kakita
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Ohtsubo
authors.forename: Ikunobu
authors.initials: I
authors.lastname: Muramatsu
authors.forename: Takafumi
authors.initials: T
authors.lastname: Nagatomo
mesh_terms: D000318:Adrenergic beta-Agonists / Q000378:metabolism; D000319:Adrenergic beta-Antagonists; D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D016466:CHO Cells; D019556:COS Cells; D002462:Cell Membrane / Q000378:metabolism; D002522:Chlorocebus aethiops; D006224:Cricetinae; D004983:Ethanolamines / Q000138:chemical synthesis / Q000378:metabolism*; D006801:Humans; D020120:Iodocyanopindolol; D007545:Isoproterenol / Q000378:metabolism; D011412:Propanolamines / Q000138:chemical synthesis / Q000378:metabolism*; D011506:Proteins / Q000378:metabolism; D011869:Radioligand Assay; D018340:Receptors, Adrenergic, alpha-1 / Q000378:metabolism*; D011943:Receptors, Adrenergic, beta / Q000378:metabolism*; D011994:Recombinant Proteins
chemical_list: D000318:Adrenergic beta-Agonists; D000319:Adrenergic beta-Antagonists; D004983:Ethanolamines; D011412:Propanolamines; D011506:Proteins; D018340:Receptors, Adrenergic, alpha-1; D011943:Receptors, Adrenergic, beta; D011994:Recombinant Proteins; D020120:Iodocyanopindolol; D007545:Isoproterenol