Minaprine

Cholinomimetic activities of Minaprine

Naunyn Schmiedebergs Arch Pharmacol 1989 Oct;340(4):411-8.2586634 10.1007/BF00167042

The cholinomimetic activities of the antidepressant drug Minaprine have been investigated, in vitro and in vivo, in rodents. Minaprine, and its metabolite SR 95070B [3-(2-morpholinoethylamino)-4-methyl-6-(2-hydroxyphenyl) pyridazine hydrochloride] selectively displaced [3H]-pirenzepine from its cortical and hippocampal binding sites, and only weakly inhibited the binding of [3H]-N-methylscopolamine in either the rat cerebellum, heart and salivary glands, or the guinea-pig ileum. In mice, none of these drugs induced the typical cholinergic side-effects up to lethal doses. Minaprine and SR 95070B antagonized rotations induced by an intrastriatal injection of pirenzepine in mice, after intraperitoneal and/or oral administration. Minaprine also antagonized atropine-induced mydriasis in mice. Both Minaprine and SR 95070B potentiated the tremorigenic effect of oxotremorine without inducing tremor when injected alone. Finally, Minaprine and SR 95070B, after parenteral and/or oral injection, antagonized the scopolamine-induced deficit in passive avoidance learning, and enhanced short-term retention in the social memory test, in rats. The muscarinic agonists arecoline, oxotremorine and RS 86 [2-ethyl-8-methyl-2,8 diazaspiro-4,5 decan-1,3 dion hydrobromide], as well as the acetylcholine esterase inhibitors physostigmine and tacrine were active in most of these models. These results indicate that Minaprine, and its metabolite SR 95070B, have cholinomimetic activities which could be, at least in part, mediated by their selective affinity for M1 muscarinic receptors. Thus Minaprine could represent a potential useful drug for the treatment of senile dementias and cognitive impairments occurring in elderly people.

[(3)H]Minaprine binding to membrane preparation from rat brain

Neurochem Int 1990;17(1):67-75.20504604 10.1016/0197-0186(90)90069-6

The specific binding site of Minaprine [3-(2-morpholino-ethylamino)-4-methyl-6-phenyl-pyridazine] in the rat brain was studied. The specific binding site of [(3)H]Minaprine was found to be mostly evenly distributed in rat brain. The affinity of [(3)H]Minaprine was highest in the hippocampus, with a dissociation constant (K(d)) of 56.3 nM, compared with the affinity in the cerebral cortex and the striatum. The specific [(3)H]Minaprine binding on a mg-protein basis was largest in the microsomal fraction. The affinity of [(3)H]Minaprine was significantly higher in the synaptosomal fraction compared with the affinity in the mitochondrial and microsomal fractions in the brain. The affinity of [(3)H]Minaprine binding was slightly increased by increasing the reaction temperature. A net increase of entropy in [(3)H]Minaprine binding was observed, accompanied by a decrease in free energy and a slight increase in enthalpy. Minaprine and an active metabolite of Minaprine, 3-(2-morpholino)-4-methyl-6-(4-hydroxyphenyl)-pyridazine (M-3), inhibited [(3)H]Minaprine binding. Neurotransmitter-related compounds all failed to inhibit [(3)H]Minaprine binding, except phencyclidine, tetraethylammonium (TEA) and 4-aminopyridine. These results suggest that Minaprine binds with high affinity to a specific binding site on the synaptic membrane, and that the site is related to a voltage-dependent K(+) channel.

Molecular mechanisms in the action of Minaprine

Prog Neuropsychopharmacol Biol Psychiatry 1988;12(5):629-37.2851858 10.1016/0278-5846(88)90008-5

1. Minaprine is a pyridazine derivative endowed with antidepressant activity, however biochemical studies following repeated administrations are still lacking. 2. Rats were administered with Minaprine (10 mg/kg i.p.) twice daily for 3 weeks. 3. In minces from the frontal cortex of rats receiving Minaprine the NE-induced cAMP accumulation is reduced suggesting that, similarly to other antidepressant treatments, Minaprine attenuates the beta-adrenergic receptor function. 4. The selective lesion of the serotonergic axons abolished such attenuation. 5. In synaptic plasma membranes prepared from rats repeatedly treated with pargyline (at doses which block MAO tipo A and B) but not with Minaprine, the number of 5HT1C and 5HT2 receptors was reduced. 6. Repeated administrations of Minaprine but not of pargyline increased the Bmax values of [3H]-imipramine binding. In 5, 7-DHT lesioned rats Minaprine failed to increase the number of the residual [3H]-imipramine recognition sites. 7. The authors conclude that the increase in the number of [3H]-imipramine recognition sites is unrelated to the IMAO activity of Minaprine. 8. The presence of 5HT axons on which [3H]-imipramine recognition sites are located is an absolute requirement for the clinical efficacy of Minaprine. 9. The action of Minaprine in the regulation of the synthesis and/or of the release of an endogenous substance that is important in mediating brain beta-adrenergic function is discussed.

Differentiation of the active site of Minaprine from that of phencyclidine in rat hippocampus

Res Commun Chem Pathol Pharmacol 1990 Jul;69(1):85-98.1977191

The active site of Minaprine (3-(2-morpholinoethylamino)-4-methyl-6-phenylpyridazine) was studied by means of receptor binding and its effect on acetylcholine (ACh) release in rat hippocampus. [3H]Minaprine binding to the hippocampal membrane was inhibited by Minaprine, 4-aminopyridine (4-AP) and phencyclidine (PCP) dose-dependently, whereas it was not inhibited by L-glutamate (L-Glu), N-methyl-D-aspartate (NMDA), 2-amino-5-phosphonovalerate (APV), 3-(3-hydroxyphenyl)-N-(1-propyl)piperidine ((+)3-PPP) or ketamine. [3H]PCP binding was inhibited by PCP and APV in an extensively washed hippocampal membrane. Minaprine, however, failed to inhibit the [3H]PCP binding. [3H]3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid (CPP) binding was inhibited by L-Glu but not by Minaprine. NMDA-evoked [3H]ACh release from the rat hippocampal slices was effectively inhibited by PCP. However, Minaprine had no effect on the NMDA-evoked [3H]ACh release. Similar results were obtained from the study of [3H]ACh release in the striatum. These results suggest that Minaprine exerts its action via the voltage-dependent K+ channel but not via the NMDA receptor-channel complex or sigma receptor.

[Minaprine]

Rev Med Univ Navarra 1984 Dec;28(4):47-8.6098950