Replacement of the isothiourea moiety of known histamine H3 antagonists by certain 5-membered heteroaromatic systems can give compounds with an improved activity profile. One of these, 3-[(4-chlorophenyl)methyl]-5-[2-(1H-imidazol-4-yl)ethyl] 1,2,4-oxadiazole (GR175737) is a potent, selective, orally active and centally penetrating H3 antagonist.

We have examined the specific binding of the tritiated derivative of the potent histamine H3 receptor antagonist, [3,4-3H2]-cyclohexyl-{[4-(3H-imidazol-4-yl)-piperidin-1-yl]iminomethyl}-amine ([3H]GR168320), to homogenates of rat cerebral cortex. Specific binding of [3H]GR168320 at 37°C associated and dissociated rapidly. Binding was saturable (Bmax 412 ± 89 fmol/mg protein) and of high affinity (Kd 0.12 ± 0.11 nM). Saturation studies suggested the involvement of a single site. Histamine H3 receptor agonists and antagonists inhibited [3H]GR168320 binding with high affinity. Agonist and antagonist affinities correlated when compared with affinities obtained using the tritiated histamine H3 agonist radioligand Nα-methylhistamine.

Since their discovery in the late 1980s, 5-HT1D receptors have aroused considerable interest, not least because they represent the most abundant 5-HT1 receptor subtype in the CNS. Until recently, studies of the 5-HT1D receptor have relied upon poorly selective agents and this has seriously hampered efforts to define their physiological and potential pathological role in the CNS. Now, a series of centrally active, selective 5-HT1D receptor antagonists have become available which should add an important dimension to the study of 5-HT1D receptors. This review provides background biology on 5-HT1D receptors and the current status of novel chemical entities.

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