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A newly synthesized agonist for muscarinic acetylcholine (ACh) receptors CS-932, (R)-3-(3-iso-xazoloxy)-1-azabicyclo-[2.2.2]octane hydrochloride, showed a relatively higher affinity for M1 than M2 receptors expressed in Chinese hamster ovary (CHO)-cells in comparison with ACh. CS-932 elevated the intracellular Ca2+ level only in M1-CHO cells, although ACh increased the level in both M1- and M3-CHO cells. CS-932 and ACh reduced forskolin-stimulated accumulation of cAMP in M2-CHO cells by 20% and 80%, respectively. This neurochemical profile of CS-932 indicates that the compound can activate M1-receptor-mediated functions selectively. CS-932 increased firing of cholinoceptive neurons in rat hippocampal slices, and this excitation was antagonized by pirenzepine, but not by AF-DX 116. CS-932 increased awake and decreased slow wave sleep episodes of daytime EEG in free-moving rats. It counteracted scopolamine-induced slow waves in rat cortical EEG. CS-932 also increased the power of alpha- and beta-waves, but decreased delta-wave of the cortical EEG in anesthetized monkeys. It ameliorated scopolamine-induced impairment of working memory in rats. Orally administered CS-932 had the best penetration into the brain among the muscarinic agonists tested and caused the least salivary secretion among the cholinomimetics examined. These results indicate that CS-932 has potential as a cognitive enhancer with fewer side effects in therapy for Alzheimer disease.

Sites of the muscle relaxant action of CS-722 were investigated in rats. Doses injected intra-4th ventricularly (i.c.v.) or intrathecally (i.t.) were determined according to measurements of CS-722 concentration in the brain stem and the spinal cord after systemic administration. When administered i.c.v. (50 and 100 micrograms) or i.t. (200 and 400 micrograms), CS-722 reduced the radio frequency decerebrate rigidity, although the effect after i.c.v. injection was transient. These results indicate that CS-722 exerts its muscle relaxant action by affecting both the supraspinal structure and the spinal cord. Spinal reflexes were not affected by CS-722 injected i.c.v. It seems that muscle relaxation is not always accompanied by impairment of the spinal reflex.

Membrane potential changes were recorded by the sucrose-gap method from the ventral as well as dorsal roots in the isolated perfused spinal cord of the frog. Cyclic AMP (l-5mM), dissolved in perfusion fluid, caused depolarization in both roots in preparations where spontaneous DC shifts were frequently observed. Adenosine phosphates (ATP,ADP,AMP ;3mM) exerted the same effects (sometimes a small hyperpolarization preceded the depolarization) in these preparations, although cyclic GMP and adenosine (3mM for each) hyperpolarized both roots. In preparations in which neurotransmission was blocked with tetrodotoxin (10-7), cyclic AMP failed to depolarize the ventral root, although ATP could still do so. Therefore, unlike the direct effect of ATP on the post-synap-tic membranes of the ventral horn cells, the excitatory effect of cyclic AMP may be trans-synaptic. In Ringer solution containing high concentration of Ca++, ATP and cyclic AMP (3mM for each) could depolarize the ventral root, although their amplitudes were greatly reduced. Therefore, their depolarizing actions may be partly ascribed to their Ca-chelating actions: but especially for cyclic AMP, the depolarizing action might be covered with decrement of spontaneous DC shifts caused by high concentration of Ca++.