Nimodipine, a Ca2+ antagonist with cerebrovasodilatory and anti-ischemic effects, binds to rat, guinea pig, and human brain membranes with high affinity (less than 1 nM). Only at higher concentrations has nimodipine been reported to block the release of some neurotransmitters and hormones from neuronal tissue. Nimodipine has no consistent effect on brain oxygen consumption or cortical ATP or phosphocreatine levels, although the ischemia-induced fall of brain ATP levels in gerbils or the lowering of intracellular brain pH in rabbits with focal cerebral ischemia were antagonized by the drug. In rats and baboons with middle cerebral artery occlusion, nimodipine was found to reduce neurological deficits without an increase in intracranial pressure or brain edema. Electrophysiological studies with nimodipine suggested a direct neuronal action. In rabbit dorsal root ganglion cells, concentrations as low as 20 nM were reported to block inward Ca2+ currents. Recent studies have suggested that nimodipine may also improve memory in brain-damaged or old rats, restore sensorimotor function and abnormal walking patterns of old rats, and accelerate acquisition of associative learning in aging rabbits. Blockade of age-related changes in Ca2+ fluxes in rat hippocampal neurones by nimodipine in vitro pointed to neuronal plasma membrane as the site of nimodipine action. The therapeutic usefulness of nimodipine appears not to be limited to cerebral ischemia, but may include dementia, age-related degenerative diseases, epilepsy, and ethanol intoxication.
The synthesis of a series of isoelectronic analogues of (S)-2-[3-(tert-butylamino)-2-hydroxypropoxy]-3-cyanopyridine (1) are described; included in this group are examples of thiazole, isothiazole, thiadiazole, pyrazine, and the structurally related naphthyridines. All of the compounds are similar to 1 in that they contain a cyano group ortho to the aminohydroxypropoxy side chain and meta to the nitrogen heteroatom. In addition, several related examples, having additional nuclear substituents and/or groups other than CN in the position adjacent to the aminohydroxypropoxy group, were prepared, and beta-adrenoceptor antagonist activity and vasodilating potency were determined. Three compounds, thiazole 2 and isothiazoles 3 and 27, effectively lowered mean arterial pressure in the SH rat at 5 mg/kg. Compounds 2, 3, and 27 increased iliac blood flow and exhibited beta-adrenergic blocking properties in the dog.
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