minaprine

Radiation molecularly transforms naturally occurring products by inducing the methoxylation, hydroxylation, and alkylation of parent compounds, thereby affecting the anti-inflammatory capacities of those compounds. Minaprine (1) modified by ionizing radiation generated the novel hydroxymethylation hydropyridazine (2), and its chemical structure was determined based on NMR and HRESIMS spectra. Compared to the original minaprine, the novel generated product showed a highly enhanced anti-inflammatory capacity inhibited nitric oxide (NO) and prostaglandin E2 (PGE2 ) production in lipopolysaccharide (LPS)-stimulated RAW 264...

Henri Laborit was one of the founders of modern neuropsychopharmacology, having discovered, or participated in, the discovery of chlorpromazine, gamma-OH, clomethiazole, and minaprine. He also put forward a theory regarding the necessity of counteracting the negative consequences of defense mechanisms during anesthesia or behavioral inhibition. The scope of his work covers neurophysiology, pharmacology, psychiatry, and psychosomatics. His independence of spirit meant that most of his research was not done within university settings...

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...

5-Hydroxytryptamine (serotonin, 5-HT) and 5-HT(2) receptor agonist 4-bromo-2,5-dimethoxyphenylisopropylamine (DOB) inhibited K(+)-induced [(3)H]acetylcholine ([(3)H]ACh) release from slices and crude synaptosomes of rat cerebral cortex. Minaprine [3(2-morpholinoethylamino)-4-methyl-6-phenylpyridazine] and the 5-HT(2) receptor antagonists, ketanserin and methysergide, had no effect on [(3)H]ACh release alone. However, they attenuated the inhibition of [(3)H]ACh release by 5-HT and DOB. The attenuating effect of 5-HT was not mimicked by the 5-HT(1A) receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), neither was it prevented by the 5-HT(1A) and 5-HT(1B) mixed receptor antagonist, propranolol, or by the 5-HT(3) receptor antagonist, cocaine...

CYP2D6 substrate status is a critical Go/No Go decision criteria in central nervous system (CNS) drug discovery efforts because the polymorphic nature of CYP2D6 can lead to variable patient safety and drug efficacy. In addition, CYP2D6 is disproportionately involved in the metabolism of CNS drugs compared with other drug classes. Therefore, identifying trends in small molecule properties of CNS-penetrant compounds that can help discriminate potential CYP2D6 substrates from nonsubstrates would allow additional prioritization in the synthesis and biological evaluation of new therapeutic candidates...

3-[(beta-morpholinoethyl)amino]-4-methyl-6-phenylpyridazine (minaprine) is an acetylcholinesterase (AChE) inhibitor. 3-Benzidino-6(4-chlorophenyl) pyridazine (BCP) and minaprine have a central pyridazine ring in common. In this study, we investigated the effects of BCP on delayed rectifier potassium current (IK(DR)) and transient outward potassium current (IK(A)) in acutely isolated rat hippocampal pyramidal neurons by using whole-cell patch-clamp technique. IK(DR) and IK(A) were inhibited by BCP (0.01-500 microM) in a concentration-dependent and voltage-dependent manner...

In this study, we utilized comparative molecular field analysis (CoMFA) to gain a better understanding of the steric and electrostatic features of the cytochrome p450 2D6 (CYP2D6) active site. The training set consists of 24 substrates with reported K(M) values from liver microsomal CYP2D6 spanning an activity range of almost three log units. The low energy conformers were fit by root mean square (RMS) to minaprine at the site of metabolism and to the protonated nitrogen. In this manner, we constructed two CoMFA models, one model with a distance constraint and another without...

The psychomotor and cardiovascular effects of minaprine 100 mg, a novel antidepressant, were compared with amitriptyline 25 mg, as a positive control, and placebo in a single dose randomised double-blind crossover trial using an automated psychomotor test battery (APT), postural sway (PS), blood pressure (BP) and pulse in nine young and nine elderly healthy subjects. Analysis of variance, taking into account baseline values, showed that continuous attention test (CAT), critical flicker fusion threshold (CFFT), decision making test (DMT) and paired word association (PWA) were significantly impaired with amitriptyline compared with minaprine and placebo...

R-(+)-Hyoscyamine (1-10 microg/kg, s.c.) dose-dependently increased the local anesthetic effect of procaine (50 microg/ml) and lidocaine (50 microg/ml) in the conjunctival reflex test in the rabbit. This potentiating effect is completely prevented by the M1 antagonist dicyclomine (10 mg/kg, s.c.). The intensity of R-(+)-hyoscyamine antinociception was comparable to that induced by morphine (2 mg/kg, s.c.) and minaprine (15 mg/kg, s.c.), used as analgesic reference drugs. In the same experimental conditions, the S-(-)-enantiomer of atropine (0...

Following the discovery of the weak, competitive and reversible acetylcholinesterase (AChE)-inhibiting activity of minaprine (3c) (IC50 = 85 microM on homogenized rat striatum AChE), a series of 3-amino-6-phenylpyridazines was synthesized and tested for inhibition of AChE. A classical structure-activity relationship exploration suggested that, in comparison to minaprine, the critical elements for high AChE inhibition are as follows: (i) presence of a central pyridazine ring, (ii) necessity of a lipophilic cationic head, (iii) change from a 2- to a 4-5-carbon units distance between the pyridazine ring and the cationic head...

A series of thienocycloheptapyridazines (3aa-dd), structurally related to Minaprine, was synthesized and compounds tested for their affinity towards muscarinic receptors. All of them showed Ki values in the micromolar range towards both the antagonist 3H-QNB and the agonist 3H-OXO-M, thus indicating that they act as antagonists at the muscarinic receptors. Moreover a theoretical study was performed on their interaction behaviour with a three dimensional (3-D) model of the human m1 muscarinic receptor.

By 1990, the Clin Midy (SANOFI) laboratory had modified the dose of Cantor tablets: the content of active drug (minaprine) increased (50 to 100 mg). Therefore, acute intoxication by minaprine can be serious, with generalized seizures, resisting the classic treatment. We tried to evaluate the possible consequences of this change of dose for the gravity of suicide attempts. 1091 voluntary acute intoxications have been collected by the national French Poisons Centres data bank, 226 of them by the Poisons center of Marseilles...

Imipramine-N-oxide, quinupramine, clomipramine, doxepin, maprotiline, amineptine, amoxapine, mianserin, minaprine, nomifensine, viloxacine, trazodone and lofepramine effects were studied on rat vas deferens responses to noradrenaline. Tissues were prepared in Krebs-Henseleit solution with and without adding cocaine. 17 beta-estradiol and propranolol for blocking neuronal and extraneuronal noradrenaline reuptake. In normal Krebs-Henseleit solution imipramine-N-oxide, nomifensine, viloxacine and lofepramine increased noradrenaline responses, while clomipramine, trazodone and doxepin behaved as competitive antagonists...

A very large number of therapeutic trials of antidepressant drugs have been reported in the scientific literature. Until now, the comparison of one drug with another, or with placebo, has been performed typically by comparing the scores on depression rating scales of the two groups of patients at fixed points of time after the beginning of therapy. It was postulated in 1989 that the curves of the recovery scores followed an exponential curve of the formula y = ae-bx + c. This hypothesis was tested in a double-blind controlled trial of the antidepressant minaprine, with the use of the scores on the Hamilton Rating Scale for Depression (HAM-D)...

1. A double-blind, multicentre study comparing the efficacy and safety of minaprine and amitriptyline in patients with major depression was carried out. Five hundred and thirty-one patients were randomly assigned to treatment with either minaprine 100 mg, 200 mg or 300 mg day-1 or with amitriptyline 150 mg day-1 (75 mg during the first week). The medication was administered for 6 weeks. 2. Efficacy was assessed using the Hamilton rating scale for depression (HDRS), the Montgomery-Asberg depression rating scale (MADRS) and visual analogue assessments of depression carried out by both the investigators and patients...

Thirty five subjects (age: 45-69 years) with subjective memory loss, without any other neuropsychiatric or somatic disease, were recruited in a phase II study. This double blind randomized versus placebo controlled study compared the effects of minaprine (200 mg/d) with placebo, in two parallel groups, during 2 months, on memory, attention and vigilance. Three psychometric tests were the main criteria of assessment: a standardized battery of memory tests (SM 5), the dual-coding test, the analysis of choice reaction times (CRT) and the critical flicker fusion point (CFF)...

There is little awareness in the United States and other English-speaking countries of a number of novel antidepressant drugs that have recently been developed and marketed in France. This review focuses on tianeptine, amineptine, minaprine, medifoxamine, and modafinil--examining both their pharmacological actions and their clinical efficacies. Their potential for further research or marketing in the United States is discussed.

Different types of clinically effective antidepressants prevent the behavioral effects of experimental stress, and some of these treatments affect mesolimbic dopamine (DA) functioning. Animal studies have demonstrated that repeated psychostimulant administration and repeated or chronic stressful experiences also affect mesolimbic DA functioning. These results could suggest homologies among stress, psychostimulants and antidepressants. The present experiments show that either repeated stress (120 min restraint daily for 10 consecutive days) or subchronic treatment with the antidepressant minaprine (5 mg/kg daily for 10 consecutive days) significantly reduced the inhibitory effect of 120 min of restraint on climbing, a behavioral response dependent on mesolimbic DA functioning...

In the search for central cholinergic agents which do not derive from already well-known agonists such as arecoline, pilocarpine or oxotremorine, we selected minaprine [3-(beta-morpholinoethylamino)-4-methyl-6-phenyl-pyridazine dihydrochloride] as a lead structure. Effectively, beside its antidepressive properties, minaprine shows a weak but highly selective affinity for hippocampic M1 receptors (IC50 = 17.10(-6) [3H]-pirenzepine). On the other hand minaprine has an excellent bioavailability and is well tolerated in human; particularly, minaprine does not induce any cholinergic syndrome...

The nootropic activity of 3-(2-morpholino-ethylamino)-4-methyl-6-phenyl-pyridazine dihydrochloride (minaprine) has been investigated in intact male, adult Long Evans rats by means of an active avoidance paradigm. In the light-dark box apparatus, the rat had to learn the active avoidance response of going out of the normally preferred dark chamber to avoid electric foot-shocks. These were administered during one trial per day for 3 consecutive days (acquisition period). After a 72-h interval, rats underwent, for 3 consecutive days, one trial per day in which punishments were omitted (retrieval period)...