AN APPROACH TO THE DESIGN OF BRAIN-PENETRATING HISTAMINERGIC AGONISTS

Known and novel histaminergic H-1- and H-2-receptor agonists were inve stigated as potentially potent and selective brain-penetrating compoun ds. Structural modifications were introduced in an attempt to favour p assive diffusion across the blood-brain barrier by reducing hydrogen-b onding ability according to a previously developed model. While no nov el compound was identified which satisfied our requirements for a brai n-penetrating agonist, betahistine 14 and 2-(thiazol-2-yl)ethylamine 1 6 can be regarded as H-1-receptor agonists with moderate brain-penetra ting ability, of potential value as pharmacological tools. A novel his tamine analogue, N,N-bis-{2-[4(5)-imidazolyl]ethyl)amine 25 is reporte d which. although unlikely to be brain penetrant, was found to be equi potent with histamine at H-1- and H-1-receptors.