Histamine H3-receptors are known to be inhibitory presynaptic autoreceptors and heteroreceptors modulating release and synthesis of other important neurotransmitters. According to the function and the relatively high receptor density in the CNS antagonistic substances might be used in the therapy of diseases of the central nervous system (e.g. ADHD, epilepsy, Alzheimer disease or schizophreny).
The starting point for the development of the substances herein described is unter anderem a patent of Schering-Plough about histamine H3 receptor antagonists containing an imdazole ring connected to different functional groups by a para-xylendiyl-spacer. Recently Ganellin et al have shown for different classes of H3 receptor antagonists that it is possible to replace the imidazole moiety by alicyclic nitrogen containing heterocycles to avoid possible interactions with CYP 450 enzymes. The para-xylendiyl-chain increaeses in comparison to the standard H3-antagonist FUB 372's propyl chain the probability to cross the blood brain barrier due to increased lipophilicity.
The presented new substances combine an alicyclic nitrogen containing heterocycle substituted in position 1 with a para-xylendiyl-spacer and a para-substituted phenoxy group and represent a new class with nanomolar affinities to the cloned human H3 receptor in vitro and high in vivo potency in the mouse. The compound combining a 2-methylpyrrolidin ring and a para-acetyl group 8 shows in this series advantageous capabilities with a Ki of 1.2 nM (hH3), an ED50 of 0.78 mg/kg p.o. (mouse) and a pA2 of 8.18 (guinea pig). In addition,substitution of the phenoxy group with an imidazol group 59 or a piperidinomethyl group shows high in vitro activity. Despite their basicity they are also highly potent in vivo. Further studies resulted in the decrease of activity in all species tested at by varying the para-xylendiyl chain to meta- and ortho-position. The phenolether moiety was found to be replaceable by other functional groups. Especially the inverse ether 68, the thioether 70 and the ester 74 reveal high in vitro activity at the human H3-receptor. In the guinea pig no significant differences in potency were detected, but in contrast to the phenolether a clear difference between methyl- and chlor-substitution is seen. In vivo only 68 is äquipotent in comparison to the lead structure.
In addition to former studies some para-substituted 3-(1H-imidazol-4-yl)propyl-phenolether and 3-(piperidin-1-yl)phenolether have been synthesized, which showed very high in vivo potency and affinity to the human H3-receptor.
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