NORDIMAPRIT, HOMODIMAPRIT, CLOBENPROPIT AND IMETIT - AFFINITIES FOR H-3 BINDING-SITES AND POTENCIES IN A FUNCTIONAL H-3 RECEPTOR MODEL

We determined the affinities of nordimaprit, homodimaprit, clobenpropi t and imetit for H-3 binding sites (labelled by H-3-N(alpha)-methylhis tamine) in rat brain cortex homogenates and their potencies at presyna ptic H-3A receptors on noradrenergic nerve endings in mouse brain cort ex slices. H-3-N(alpha)-Methylhistamine bound saturably to rat brain c ortex homogenates with a K(d) of 0.70 nmol/l and a B(max) of 98 fmol/m g protein. Binding of H-3-N(alpha)-methylhistamine was displaced monop hasically by dimaprit (pK(i) 6.55), nordimaprit (5.94), homodimaprit ( 6.44), clobenpropit (9.16), imetit (9.83), R-(-)-alpha-methylhistamine (8.87) and histamine (8.20), and biphasically by burimamide (pK(i) hi gh 7.73, pK(i) 1, 5.97). In superfused mouse brain cortex slices prein cubated with H-3-noradrenaline, the electrically (0.3 Hz) evoked triti um overflow was inhibited by imetit (pIC35 8.93), R-(-)-alpha-methylhi stamine (7.87) and histamine (7.03). The effect of histamine was atten uated by nordimaprit, homodimaprit, clobenpropit and N-ethoxycarbonyl- 2-ethoxy-1,2-dihydroquinoline (EEDQ); EEDQ (but not nordimaprit, homod imaprit and clobenpropit) attenuated the effect of histamine also in s lices pre-exposed to the drug 60-30 min prior to superfusion. The conc entration-response curve of histamine was shifted to the right by homo dimaprit and clobenpropit; Schild plots yielded straight lines with a slope of unity for both drugs (pA2 5.94 and 9.55, respectively). Nordi maprit depressed the maximum effect of histamine (pD'2 5.55) and also slightly increased the concentration of histamine producing the half-m aximum effect. In conclusion, nordimaprit and homodimaprit possess sim ilar affinities for H-3 binding sites like dimaprit; nordimaprit and h omodimaprit as well as clobenpropit and imetit do not differentiate be tween H-3A and H-3B binding sites. Nordimaprit is a reversible noncomp etitive H-3 receptor antagonist, homodimaprit and clobenpropit are rev ersible competitive H-3 receptor antagonists and imetit is an H-3 rece ptor agonist.