title: The four stereoisomers of a high potency congener of isoproterenol. Biological activity and the relationship between the native and the chemically inserted asymmetric carbon.
abstract: The RR isomer of a para-trifluoromethyl anilide congener of isoproterenol (PTFMA) had an affinity eighty and one hundred times higher than (-)isoproterenol for the beta receptor of turkey erythrocytes and of S49 cells respectively. This affinity was also much higher than that of +/- hydroxybenzyl isoproterenol (HBI) tested in the same experiments. The chemically inserted asymmetric carbon seemed to be as important as the native asymmetric carbon of the catecholamines in determining the binding affinity. Thus the RS and SR isomers demonstrated similar affinities in the turkey erythrocyte membranes as well as in the S49 lysed cells. The RR isomer had the lowest Kact in activation of adenylate cyclase in both beta receptor systems. The three most potent PTFMA isomers showed a Kact/Kd ratio which was higher than that of (-)isoproterenol or (+/-)HBI. It is therefore possible that the large substituent on the amino group in PTFMA, which greatly increases the binding affinity, is not as efficient in receptor activation. Yet the RR isomer had a Kact considerably lower than that of (-)isoproterenol in both of the beta receptor systems. The type of beta receptor of the turkey erythrocyte could be distinguished from that of the S49 cells by comparing the relative order of affinities of the RS and SR isomers and also by comparing (+/-)HBI with (-)isoproterenol. A labeled RR isomer of PTFMA could become most useful as an agonist ligand for beta receptors because of its very high binding affinity for both beta 1 and beta 2 receptors.
authors.affiliation: Department of Biological Chemistry, Hebrew University of Jerusalem, Israel.
authors.forename: S
authors.initials: S
authors.lastname: Eimerl
authors.forename: M
authors.initials: M
authors.lastname: Schramm
authors.forename: S
authors.initials: S
authors.lastname: Lok
authors.forename: M
authors.initials: M
authors.lastname: Goodman
authors.forename: M
authors.initials: M
authors.lastname: Khan
authors.forename: K
authors.initials: K
authors.lastname: Melmon
mesh_terms: D000262:Adenylyl Cyclases / Q000032:analysis; D000818:Animals; D004912:Erythrocytes / Q000378:metabolism; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000031:analogs & derivatives / Q000378:metabolism*; D007700:Kinetics; D011943:Receptors, Adrenergic, beta / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014422:Turkeys
chemical_list: D011943:Receptors, Adrenergic, beta; C015272:hydroxybenzylisoproterenol; D000262:Adenylyl Cyclases; D007545:Isoproterenol