Factors controlling beta 1-adrenoceptor affinity and selectivity.
A membrane preparation of the calf heart left ventricle has been used after identification and characterization, as a source of myocardial beta 1-adrenoceptor for radioligand binding studies. The displacement of specifically bound (-)-[3H]dihydroalprenolol by some beta-adrenoceptor ligands appeared to be pH-dependent, which could be related to the ionization characteristics of the compounds. Among the usually four ionic species of the ligand, present at physiological pH, the cation was shown to govern beta 1-adrenoceptor affinity. Furthermore, quantitative structure affinity relationships for the interaction with beta 1- and beta 2-adrenoceptors were established for the phenoxypropanolamines, a class of beta-adrenoceptor ligands. The N-isopropyl-oxypropanolamine side chain itself does not discriminate between beta 1- and beta 2-adrenoceptors, whereas aromatic substitution ortho to the side chain induces some beta 2-selectivity. Selectivity for myocardial beta 1-adrenoceptors is mainly obtained by aromatic substitution para to the side chain. This substitution pattern yields a decrease in beta 2-adrenoceptor affinity, far more pronounced than the decrease in beta 1-adrenoceptor affinity.
Ijzerman
A P
AP
Dorlas
R
R
Aué
G H
GH
Bultsma
T
T
Timmerman
H
H
D000818:Animals; D002417:Cattle; D004082:Dihydroalprenolol / Q000378:metabolism; D006165:Guanylyl Imidodiphosphate / Q000494:pharmacology; D006863:Hydrogen-Ion Concentration; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000494:pharmacology; D007700:Kinetics; D009206:Myocardium / Q000378:metabolism; D011943:Receptors, Adrenergic, beta / Q000032:analysis / Q000378:metabolism*; D013329:Structure-Activity Relationship; D014316:Tritium
D011943:Receptors, Adrenergic, beta; D014316:Tritium; D006165:Guanylyl Imidodiphosphate; D004082:Dihydroalprenolol; D007545:Isoproterenol