Vinconate (Chanodesethylapovinc amine)

(+-)-Methyl-2,3,3a,4-tetrahydro-1H-indolo [3,2,1-de] [1,5] naphthyridine-6-carboxylate monohydrochloride facilitates phosphatidylinositol hydrolysis: possible involvement of muscarinic and nonmuscarinic mechanisms

The stimulation of the formation of inositol phosphate (IP) by (+-)-methyl-2,3,3a,4-tetrahydro-1H-indolo [3,2,1-de] [1,5] naphthyridine-6-carboxylate monohydrochloride (vinconate), a novel indolonaphthyridine derivative, was studied using both cerebral cortical slices and crude synaptic membranes prepared from the rat brain. Vinconate (10 mM-1 mM) inhibited the binding of [3H]quinuclidinyl benzilate to the muscarinic receptor in a dose-dependent manner and the IC50 value for [3H]quinuclidinyl benzilate binding was found to be 17 microM. The rightward shift of the inhibition curve of [3H]quinuclidinyl benzilate binding by carbachol in the presence of GTP (100 microM) was abolished by vinconate (100 microM). Carbachol (10 nM-10 mM) significantly increased [3H]IP formation in a dose-dependent manner and the rate of [3H]IP formation mediated by carbachol stimulation was significantly accentuated in the presence of 10 microM vinconate. The enhancement of [3H]IP accumulation by vinconate was inhibited by approximately 50% in the presence of atropine (1-1000 microM), although up to 1 mM of phentolamine and ketanserin had no effect on the vinconate-induced increase of phosphatidylinositol turnover. Moreover, vinconate significantly accentuated 20 mM KCl-evoked stimulation of [3H]IP formation. Vinconate had no differential effect on the ratio of IP or inositol 1,4-biphosphate and inositol 1,4,5-triphosphate formations. These results suggest that vinconate may induce a facilitation of phosphatidylinositol turnover via the stimulation of muscarinic receptors and a facilitation of coupling between muscarinic receptors and GTP-binding protein. The presence of a direct stimulatory effect of vinconate on phosphatidylinositol turnover has also been suggested.

Effect of vinconate, an indolonaphthyridine derivative, on dopamine and serotonin concentrations in dialysate from the striatum of freely moving rats: brain microdialysis studies

The effect of (+/-)-methyl 3-ethyl-2,3,3a, 4-tetrahydro-1H-indolo[3,2,1-de][1,5]naphthyridine -6-carboxylate monohydrochloride (vinconate), an indolonaphthyridine derivative, on dopamine and serotonin concentrations in dialysate from the striatum of freely moving rats was examined by brain microdialysis. Twenty-minute samples collected were used to determine dopamine and serotonin by high-performance liquid chromatography in a single run. The basal extracellular levels of dopamine and serotonin were 41.12 +/- 5.04 and 10.41 +/- 1.71 (fmol/20 min), respectively. Dopamine concentrations in dialysate were significantly increased after a single treatment with vinconate (50-200 mg/kg p.o.). Tetrodotoxin (10 microM) added into the dialysis perfusate decreased dopamine concentrations in dialysate and vinconate had no effect on dopamine concentrations in dialysate when administered after tetrodotoxin. The vinconate-induced increase in dialysate dopamine concentrations was significantly reduced by scopolamine (1 microM) and N0434 (1 microM), respectively. Moreover, daily treatment with vinconate (25 mg/kg p.o.) for 7 days resulted in enhanced dopamine and serotonin concentrations in dialysate induced by subsequent vinconate treatment. These findings suggest that vinconate administered systemically can enhance dialysate dopamine concentrations and this effect may be related to the muscarinic receptor and the dopamine D2 receptor. The present findings also suggest that repeated treatment with vinconate may augment these effects of vinconate on dopamine and serotonin concentrations in dialysate from the brain.

Effect of vinconate on the extracellular levels of dopamine and its metabolites in the rat striatum: microdialysis studies

The effects of (+/-)-methyl-3-ethyl-2,3,3 alpha, 4-tetrahydro-1H- indolo[3,2,1-de][1,5]naphthyridine-6-carboxylate hydrochloride (vinconate), an indolonaphthyridine derivative, on the extracellular levels of dopamine and its metabolites in the rat striatum were examined using brain microdialysis. Single administration of vinconate (10, 100 mg/kg i.p.) increased the extracellular level of dopamine and its metabolites. This enhancing effect of vinconate was antagonized by scopolamine (10 microM), a muscarinic receptor antagonist, which was added to the perfusate from 30 min before vinconate treatment. These findings suggest that vinconate, even when systemically administered, enhances the endogenous release of dopamine in the striatum, probably via the stimulation of presynaptic muscarinic receptors.

Effects of vinconate on scopolamine-induced memory impairment in rhesus monkeys

Effects of vinconate on specifically impaired short-term memory were studied in rhesus monkeys. Monkeys were trained to perform for orange juice reinforcement under a matching-to-sample response procedure. In the procedure, monkeys had to choose one of two stimuli that had the same color as the sample stimulus. Half of a daily session consisted of simultaneous trials where the sample stimulus was present during the time of choice. The other half of the session consisted of delayed trials where the sample stimulus had been presented but withheld at the time of choice. After the repeated training, the matching-to-sample responses were established with the percentage of correct choice responses (CR%) in both types of trials exceeding 90%. The doses of scopolamine, intervals between administration of this drug and the start of test session, and delay times in delayed trials were adjusted from one monkey to another so that delayed matching-to-sample responses were impaired by scopolamine while simultaneous matching-to-sample responses were less impaired by this drug. Scopolamine (32 or 45 micrograms/kg, s.c.) decreased the CR% for delayed trials more markedly than the CR% for simultaneous trials in four monkeys. Intragastrically administered vinconate at 16 mg/kg attenuated the scopolamine-induced short-term memory impairment. These results suggested that vinconate possesses specific ameliorating action on memory impairment caused by hypofunction of the cholinergic system in the brain.

Effect of vinconate, an indolonaphthyridine derivative, on metabolism and function of cerebral cholinergic neurons in rat

Effects of (+/-)-methyl 3-ethyl-2,3,3a,4-tetrahydro-1H-indolo [3,2,1,-de] [1,5] naphthyridine-6-carboxylate hydrochloride (vinconate), an indolonaphthyridine derivative, on the metabolism and function of cerebral cholinergic neurons were investigated using male Wistar rats. Single administration of vinconate (5, 50 and 200 mg/kg) decreased acetylcholine content in the striatum but not those in the cerebral cortex and hippocampus. The same treatment with vinconate (5, 50 and 200 mg/kg, p.o.) had no effect on the activities of choline acetyltransferase and acetylcholinesterase in these brain areas. Although the addition of vinconate (10(-7) - 10(-4) M) had no effect on the high affinity uptake of [3H]choline into striatal slices, it induced a concentration-dependent increase of a KCl(2 x 10(-2) M)-evoked endogenous acetylcholine release. The addition of (-)-sulpiride (10(-8) - 10(-6) M), a dopamine D2 receptor antagonist, also accentuated the KCl(2 x 10(-2) M)-evoked endogenous acetylcholine release form striatal slices. Furthermore, it was found that this (-)-sulpiride (10(-7) M)-induced increase of endogenous acetylcholine release was further augmented by the addition of vinconate (10(-5) M). These results suggest that vinconate may enhance the release of endogenous acetylcholine via the modulation of presynaptic dopamine heteroreceptor in the striatum.