Pharmacological analysis of immepip and imetit homologues.: Further evidence for histamine H3 receptor heterogeneity?

Following a previous report by our research group on discriminative properties of a series of aliphatic histamine homologues, we now studied immepip, imetit and its lower and higher sidechain homologues as ligands for the histamine H-3 receptor in a [I-125]-iodophenpropit binding assay using rat cerebral cortex membranes, and two functional H-3 receptor models (inhibition of the neurogenic contraction of the guinea pig jejunum and inhibition of [H-3]-noradrenaline release in rat cerebral cortex slices). The immepip homologues behaved as competitive H-3-receptor antagonists in both functional systems. The potencies (pA(2) values) observed at the guinea pig jejunum were 8.4 and 6.2 for the immepip homologues VUF 4929 and VUF 4735, respectively, whereas on the electrically evoked release of [H-3]-noradrenaline from cortical slices the pA(2) values were 7.1 and 5.5 for VUF 4929 and VUF 4735, respectively. Moreover, immepip. but not the (R)-alpha -methylhistamine, showed almost a tenfold higher agonistic potency in the rat cerebral cortex than in the guinea pig jejunum. For imetit and its homologues important discrepancies in the potencies in the two functional assays were noticed as well. VUF 8328 acts as a potent (pD(2) = 8.0) partial agonist in the brain, but as a very active (pA(2) = 9.4) competitive antagonist in the guinea pig jejunum. The partial agonistic activity of VUF 8328 in the brain was confirmed by GTP gammaS-sensitive, biphasic displacement of [I-125]-iodophenpropit binding to rat cerebral cortex membranes. The differences in potencies shown by the various ligands are discussed in relation to H-3 receptor heterogeneity. (C) 2001 Elsevier Science B.V. All rights reserved.