Radioligand binding studies with 3-(4-(2-hydroxy-3-((1, 1-dimethylethyl)-amino)-propoxy)-phenyl)-7-methoxy-2-methyl- 1(2H)-isoquinolinone (HI-42), a new cardioselective beta-adrenoceptor blocker with long-lasting effects in vivo.
The effects of 3-(4-(2-hydroxy-3-((1, 1-dimethylethyl)-amino)-propoxy)-phenyl)-7-methoxy-2-methyl-1 (2H)-isoquinolinone (HI-42), a cardioselective beta-adrenoceptor antagonist with a long duration of action in vivo, on 3H-dihydroalprenolol (3H-DHA) binding of partially purified rat cardiac membranes were investigated. In vitro, HI-42 displaced 3H-DHA from specific binding sites on the membranes in a non-competitive, reversible manner, yielding Ki-values of 43 and 1626 nmol/l for beta 1- and beta 2-receptors, respectively. After pretreatment in vivo with a single dose of 40 mg/kg HI-42 i.p., the apparent number of beta-adrenoceptors (Bmax of specific 3H-DHA binding) was significantly reduced for up to 4 days, whereas the affinity of the 3H-DHA binding sites (KD) remained unaffected. Similarly as in the in-vitro experiments, the beta-adrenoceptor blocking compound could be removed also after in-vivo pretreatment by extensive washing of the membranes. It is proposed that the long duration of action of HI-42 in vivo is due to the formation of a tight complex with beta 1-adrenoceptors; the bulky lipophilic part of the HI-42 molecule may be responsible for its slow dissociation from the receptor.
Jackisch
R
R
Lederle
M
M
Hertting
G
G
D000319:Adrenergic beta-Antagonists / Q000378:metabolism*; D000818:Animals; D001667:Binding, Competitive; D004082:Dihydroalprenolol; D066298:In Vitro Techniques; D007546:Isoquinolines / Q000378:metabolism; D007700:Kinetics; D008297:Male; D009206:Myocardium / Q000378:metabolism; D011412:Propanolamines; D011869:Radioligand Assay; D051381:Rats; D011919:Rats, Inbred Strains; D011943:Receptors, Adrenergic, beta / Q000187:drug effects / Q000378:metabolism*
D000319:Adrenergic beta-Antagonists; D007546:Isoquinolines; D011412:Propanolamines; D011943:Receptors, Adrenergic, beta; D004082:Dihydroalprenolol; C045062:HI 42