An approach to the design of brain-penetrating histaminergic agonists

Abstract Known and novel histaminergic H 1 - and H 2 -receptor agonists were investigated as potentially potent and selective brain-penetrating compounds. Structural modifications were introduced in an attempt to favour passive diffusion across the blood-brain barrier by reducing hydrogen-bonding ability according to a previously developed model. While no novel compound was identified which satisfied our requirements for a brain-penetrating agonist, betahistine 14 and 2-(thiazol-2-yl)ethylamine 16 can be regarded as H 1 -receptor agonists with moderate brain-penetrating ability, of potential value as pharmacological tools. A novel histamine analogue, N,N -bis-{2-[4(5)-imidazolyl]ethyl}amine 25 is reported which, although unlikely to be brain penetrant, was found to be equipotent with histamine at H 1 - and H 1 -receptors.

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