The unusual binding properties of the endothelin receptor antagonist CGS 27830 distinguishes receptor/agonist interactions.

CGS 27830 [meso-1,4-dihydro-5-methoxycarbonyl-2,6-dimethyl-4-(3- nitrophenyl)-3-pyridine carboxylic acid anhydride] is a nonpeptidic, insurmountable, endothelin (ET) receptor antagonist with approximately 10- to 20-fold selectivity for ETA receptors. CGS 27830 exhibits unusual binding properties which depend on the receptor and ligand: standard saturation binding experiments (coincubation of membranes with ligand in the absence or presence of antagonist) suggest that CGS 27830 is a competitive inhibitor of [125I]IRL 1620 binding to ETB receptors in rat cerebellar membranes (i.e., there was a change of apparent Kd with no change of maximum binding), but a noncompetitive inhibitor of [125I]IRL 1620 binding to ETB receptors in rat lung membranes (i.e., significant loss of total binding was observed). Although the antagonist appears to be a noncompetitive inhibitor of [125I]IRL 1620 binding to ETB receptors in rat lung membranes, CGS 27830 appears to be a competitive inhibitor of [125I]ET-1 binding to the same receptors as well as to ETA receptors in A7r5 cell membranes. Thus, CGS 27830 can distinguish [125I]IRL 1620 binding to ETB receptors in rat cerebellar and lung membranes, but not ET-1 binding to ETB receptors in these tissues. These unusual binding properties demonstrate that rat lung and cerebellum ETB receptors interact differently with IRL 1620 or ET-1.

Effect of a novel series of macrocyclic hypolipidemic agents on plasma lipid and lipoprotein levels of four non-primate species.

The ansamycins are structurally novel hypolipidemic agents derived from rifampicin, but lacking antibacterial activity. Oral or intravenous administration resulted in rapid lowering of plasma cholesterol in rats, hamsters, guinea pigs and dogs. In the chow-fed rat, three related compounds (CGP 43371, CGS 23810 and CGS 24565) exhibited ED50 values of 13.7, 3.1 and 0.18 mg/kg, respectively. A feature common to the lipid lowering documented in these four species was the concomitant reduction of low density lipoprotein (LDL) and high density lipoprotein (HDL) cholesterol. In the chow-fed rat, however, apolipoprotein AI (apo AI) levels were much less affected than were those of HDL cholesterol. CGP 43371 at 3 and 10 mg/kg, lowered HDL cholesterol by 20% and 39%, respectively, whereas plasma apo AI was reduced by only 1% and 12%. Similarly, in lipoprotein fractions separated by ultracentrifugation, apo AI was unchanged in the d = 1.019-1.21 g/ml fraction after treatment with 3 or 10 mg/kg of CGP 43371, but HDL cholesterol was reduced 12% and 26% in this fraction at the two dose levels. Plasma and lipoprotein apo B levels, on the other hand, were reduced to a level equivalent to that of the reduction in cholesterol. The ansamycins thus represent a new structural series which may possess a novel mechanism of action as well, involving differential effects on HDL cholesterol and protein.