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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.

In order to evaluate learning and memory deficits separately from and simultaneously with motivational, motor and sensory impairments in identical animals, we developed the allocentric place discrimination task test using a water maze in rats. For this assessment task, two similar, visible platforms, one was fixed and the other was floating, were simultaneously present in a pool, and the working memory of the allocentric place discrimination task was evaluated. After training, the task accuracy was high about 85% correct and animals were used repeatedly. The accuracy decreased significantly when the pool was surrounded with a black curtain. Muscarinic receptor antagonist scopolamine 0.5 mg/kg selectively impaired the accuracy. Muscle relaxant dantrolene 10 mg/kg selectively decreased swimming speed. Under low motivational condition (warm water), still time increased and swimming speed decreased, but the accuracy was not affected. Similar to warm water, opioid receptor agonist morphine 15 mg/kg increased still time and decreased swimming speed. These results suggest that the allocentric place discrimination task is useful in evaluating spatial working memory ability independently of and concurrently with also visual, motor ability and motivation in identical animals.

RS-8359, (+/-)-4-(4-cyanoanilino)-5,6-dihydro-7-hydroxy-7H-cyclopenta[d]-py rimidine, inhibits, selectively and reversely, A-type monoamine oxidase (MAO-A). In order to clarify the stereoselective metabolism of this drug, plasma concentrations of the [R] and [S]-enantiomers of RS-8359 were determined by chiral column HPLC after oral administration of each enantiomer to rats, mice, dogs, and monkeys. After administration of the [R]-enantiomer, high levels were retained in all animal species studied. On the other hand, when the [S]-enantiomer was administered, plasma concentrations decreased rapidly in rats and mice, and extremely rapidly in dogs, while in monkeys, only a trace amount was detected immediately after dosing. Thus, it was found, as a common phenomenon in rats, mice, dogs, and monkeys, that plasma concentrations of the [S]-enantiomer were markedly lower than those of the [R]-enantiomer. Secondly, the [R]-enantiomer was observed in plasma after administration of the [S]-enantiomer, and the [S] to [R] chiral inversion rate was estimated from AUC([R] after [S])/AUC([R] after [R]). The percentage was 45.8% in rats, 3.8% in mice, 0.8% in dogs, and 4.2% in monkeys. Further, the [S]-enantiomer was detected in plasma of SD rats dosed with the [R]-enantiomer, suggesting [R] to [S] chiral inversion in rats. These results show marked species differences in the chiral inversion of the cyclopentanol group of RS-8359. A mechanism of chiral inversion is discussed based on experiments using isolated rat hepatocytes.

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.

Effects of a new minor tranquilizer, CS-386 and diazepam were studied upon the gastric contraction and excitation of lumbar gamma-motoneurons following stimulation of some of the brain structures as well as upon the spontaneous gastric motility in the cat. CS-386 inhibited the hypothalamus-induced gastric contraction with little changes in spontaneous motility at doses of 5 and 10 mg/kg (i.d.). Diazepam inhibited both the hypothalamus-induced contraction and spontaneous motility at these doses. The vagal nerve-induced gastric contraction was suppressed by diazepam (5 mg/kg, i.d.) but not by the same dose of CS-386. Bemegride (5 mg/kg, i.v.) antagonized almost completely the depression caused by 5 mg/kg of CS-386, but not that by a dose of 10 mg/kg or 5 as well as 10 mg/kg of diazepam. Excitation of the lumbar gamma-motoneuron following stimulation of the posterior hypothalamus or the mesencephalic reticular formation was depressed by CS-386 or diazepam (10 mg/kg, p.o.), but not by lower doses. Based on the these evidences, it was suggested that CS-386 could be effective in stress-induced gastric lesions with lower side effects in digestive organs than diazepam.

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++.