Modulation of neurotransmitter release via histamine H₃ heteroreceptors

Abstract

Presynaptic H3 receptors occur on histaminergic neurones of the CNS (autoreceptors) and on non-histaminergic neurones of the central and autonomic nervous system (heteroreceptors). H3 heteroreceptors, most probably located on the postganglionic sympathetic nerve fibres innervating the resistance vessels and the heart, have been identified in the model of the pithed rat. Furthermore, we could show in superfusion experiments that H3 heteroreceptors also occur on the sympathetic neurones supplying the human saphenous vein and the vasculature of the pig retina and on the serotoninergic, dopaminergic and noradrenergic neurones in the brain of various mammalian species, including man. The effects of three recently described H3 receptor ligands were studied in superfused mouse brain cortex slices. The potency of the novel H3 receptor agonist imetit exceeded that of R-(-)-alpha-methylhistamine (the reference H3 receptor agonist) by one log unit and that of histamine by almost two log units. Clobenpropit was shown to be a competitive H3 receptor antagonist, exhibiting a pA2 as high as 9.6 (exceeding the pA2 of the reference H3 receptor antagonist thioperamide by one log unit). The irreversible antagonism of N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) was also studied. Interactions of the H3 heteroreceptor with the dopamine autoreceptor in mouse striatal slices and the alpha 2-autoreceptor in mouse brain cortex slices could be demonstrated. Activation of alpha 2-autoreceptors decreases the H3 receptor-mediated effect. Blockade of alpha 2-autoreceptors increases the H3 receptor-mediated effect only if the alpha 2-autoreceptors are simultaneously activated by endogenous noradrenaline. The H3 receptor-mediated inhibition of noradrenaline release in mouse brain cortex slices was attenuated by the K+ channel blocker tetraethylammonium but this attenuation was abolished by reduction of the Ca2+ concentration in the medium (to compensate for the facilitatory effect of tetraethylammonium on noradrenaline release). Accordingly, we assume that the H3 receptors are not coupled to voltage-sensitive K+ channels. Pertussis toxin and N-ethylmaleimide attenuated the H3 receptor-mediated effect in the mouse brain cortex, suggesting that the H3 receptors are coupled to a G protein (eg Gi or Go). However, negative coupling to an adenylate cyclase does not appear to exist since an H3 receptor-mediated inhibition of cAMP accumulation was not obtained in mouse brain cortex membranes. H3 receptor ligands are currently undergoing clinical testing and might become new remedies for the treatment of disease of the gastrointestinal and bronchial system and the CNS.

D‐Amino Acid Homopiperazine Amides: Discovery of A‐320436, a Potent and Selective Non‐Imidazole Histamine H3‐Receptor Antagonist

“…Compound 3 was next treated with 2,5-dibromopyridine and NaH in methyl sulfoxide (DMSO) to afford inter- mediate 4 (80 % yield). A Suzuki cross-coupling reaction [19] of 4 with 4-cyanophenyl boronic acid was used next to generate compound 5, followed by treatment with trifluoroacetic acid (TFA) in dichloromethane (DCM) which gave 4-[6-(3- [1,4] diazepan-1-yl-propoxy)-pyridin-3-yl]-benzonitrile (6) in 90 % yield.…”

Synthesis of Potent Non-imidazole Histamine H3-Receptor Antagonists

“…betahistine [12] (K i = 7 µM), phencyclidine [13] (K i = 13 µM), dimaprit [14] (K i = 3 µM), the pyridine analogue of thioperamide [15] (K i = 13 µM), and clozapine [16] (K i = 0.7 µM). Generally, however, replacement of the imidazole ring in H 3 antagonists by other heterocycles is accompanied by a loss of activity [17,18] . It should be possible to obtain non-imidazole antagonists using one of the foregoing compounds as a lead even though they are only weakly active and, indeed, this approach has very recently been reported in posters [19] starting from the compound sabeluzole [20] (Chart 1), which is a benzothiazole derivative.…”

“…Inhibition of the action of histamine at the H 3 receptor therefore increases the concentration released of the histamine neurotransmitter. The H 3 receptors also occur as heteroreceptors [3] on non-histaminergic neurones modulating the release of other neurotransmitters in the brain and periphery.…”

“…A few weakly active non-imidazole compounds have been described as H 3 antagonists, e.g. betahistine [12] (K i = 7 µM), phencyclidine [13] (K i = 13 µM), dimaprit [14] (K i = 3 µM), the pyridine analogue of thioperamide [15] (K i = 13 µM), and clozapine [16] (K i = 0.7 µM).…”

Synthesis and Stability in Biological Media of 1H‐Imidazole‐1‐carboxylates of ROS203, an Antagonist of the Histamine H3 Receptor

“…Introduction. -The histamine H 3 receptor, discovered in the early 1980s [1], then cloned and characterized in 1999 [2], is a G-protein-coupled auto-and heteroreceptor (GPCR) regulating the synthesis and release of histamine [3] and of other important neurotransmitters such as acetylcholine, norepinephrine, dopamine, and serotonin [4]. It exhibits low sequence similarity (ca.…”