Studies on the biochemical mode of action of EGYT-475, a new antidepressant

We studied the mode of action of N-benzyl-piperazine-picolinylfumarate (EGYT-475) and of its metabolite N-benzyl-piperazine (EGYT-2760) in CFY rats. It was found that EGYT-475 had no uptake-inhibitory effect but EGYT-2760 inhibited the high-affinity uptake of 3H-noradrenaline, 3H-dopamine and especially that of 3H-serotonin both in vitro and ex vivo. Neither of the two compounds changed the serotonin turnover. Only EGYT-2760 evoked hyperthermia in rats at a high ambient temperature (28 degrees C). This effect was abolished by cyproheptadine but not by amitriptyline. EGYT-2760 antagonized serotonin-induced contractions of the stomach fundus but it was inactive in inhibiting the serotonin-induced platelet aggregation. Our results suggest that EGYT-2760, an active metabolite of EGYT-475, has a central serotoninomimetic action which involves 5-HT uptake-inhibition and 5-HT1 receptor agonistic effect.     

Studies for the elucidation of the mode of action of the antimycotic hydroxypyridone compound, rilopirox.

Rilopirox is a synthetic, fungicidal antimycotic agent with hydrophobic characteristics. Its chemical name is 6-[4-(4-chlorophenoxy)-phenoxy-methyl]-1-hydroxy-4-methyl-2-pyridone and it has a molecular weight of 357.79. Rilopirox is very soluble in dimethyl sulfoxide (DMSO) and dimethylformamide (DMF) but poorly soluble in water. The amount of antimycotic agent remaining in the solution is dependent on the final concentration of the solvent and the amount of rilopirox used. Complexometric studies show that rilopirox has a high affinity for iron ions [unpubl. data]. Catalase, an iron-containing enzyme, is inhibited by the chelating agent rilopirox. Studies on yeast mitochondria and submitochondrial particles show that rilopirox inhibits the respiratory chain. Complex I (NADH-ubiquinone oxidoreductase) contains iron-sulfur proteins and is the main system which is inhibited.     

Studies on the antagonism by raphe lesions of the antinociceptive action of systemic morphine.

In rats, lesions were placed in the dorsal/median raphe (DMR), in the ventral raphe (VR: raphe magnus), in both the dorsal/median and ventral raphe (DMVR) or in the reticular formation (RF). The effect of the lesions on the antinociception and catalepsy produced by 3 doses of morphine (3, 10 and 30 mg/kg) was examined. The lesions had no significant effect on the catalepsy produced by any of the doses of morphine tested. DMR lesions produced a partial attentuation of the antinociceptive action of both the 3 and 10 mg doses. VR lesions produced a complete blockade of the 3 mg and only a partial attenuation of the 10 mg dose. In contrast, the combined (DMVR) lesions yielded virtually a total blockade of the 3 and 10 mg. Yet, as with the DMR and VR groups, the DMVR lesions failed to produce a significant antagonism on either of the nociceptive tests at the 30 mg dose. These findings suggest that the ascending and descending fiber systems emanating from the dorsal/median and ventral raphe, respectively, facilitate the expression of morphine-induced analgesia but that neither system alone can be regarded as essential for the manifestation of the antinociceptive effects of systematically administered morphine.     

Involvement of dopamine in the mechanism of action of FR64822, a novel non-opioid antinociceptive compound.

A novel compound, FR64822(N-(4-pyridylcarbamoyl)amino 1,2,3,6,-tetrahydropyridine), displays antinociceptive activities in a variety of assays with mice and rats. It has a strong antinociceptive activity in the acetic acid writhing test (ED50 = 1.8 mg/kg p.o.), whereas it has little antinociceptive activity in the tail flick test. The antinociceptive profile is similar to that of nefopam but different from that of anti-inflammatory agents. The involvement of monoamines in the mechanism of action of FR64822 was investigated. Pretreatment with reserpine (2 mg/kg) significantly reduced the antinociceptive activity of FR64822, when tested against acetic acid writhing. A similar reduction of activity was found in mice pretreated with sulpiride (10 mg/kg), a dopamine D2 receptor antagonist, but not with Sch23390 (0.25 mg/kg), a dopamine D1 receptor antagonist. Pretreatment with p-chlorophenylalanine, yohimbine and naloxone hardly affected the antinociceptive activity of FR64822. These results were compared with those for nefopam and clonidine. It is suggested that FR64822 induces antinociceptive activity through a novel mechanism of action, indirect stimulation of dopamine D2 receptors, which differs from that of nefopam in that no specific neurotransmission could be determined in nefopam analgesia.     

Studies on the mode of action of methyridine

Methyridine [2-(β-methoxyethyl)pyridine] reached the blood and all regions of the alimentary canal following oral or subcutaneous administration of therapeutic doses of the drug. Concentrations in the lower gut were highest following subcutaneous administration, and there was a close association between blood and intestinal levels suggesting that the drug is excreted into the alimentary canal along its whole length. In vitro experiments with intact nematodes (Ostertagia spp. from sheep; Nematospiroides dubius and Heterakis spumosa from mice; and Nippostrongylus muris from rats) and with preparations of Ascaris sp. have demonstrated that methyridine passes through the cuticle and exerts an “irreversible” paralysing effect on the worms. This action is obtained within 1 hr at concentrations similar to peak levels shown to be present in the alimentary canal following the administration of therapeutic doses. Concentrations of the drug were found to be higher in the abomasum than in the intestine of sheep and yet the anthelmintic activity of methyridine is greatest against intestinal nematodes. No significant differences in the resistance of various nematode species to the drug were demonstrated, but the amount of methyridine entering ascarids was significantly greater at pH 8 than at pH 5 or 3. In addition, the in vitro anthelmintic activity of the compound was greatest in alkaline solutions, which probably accounts for the differences in anthelmintic activity noted in various parts of the alimentary canal. The paralysing effect of methyridine on nematodes is probably due to a neuromuscular block of the decamethonium type, and this can also be produced in the host by over-dosage. It is suggested that nematode tissues are more sensitive to this action than vertebrate tissues.     

Studies on Centchroman,a new antifertility compound

This paper reports the results of laboratory research on the chemical properties, analytic specifications, assay method, and stability of centchroman--3,4-trans-2,2-Dimethyl-3-phenyl-4(p-beta-pyrrolidinoethoxy)-7-methoxychromanhydrochloride. This compound has been reported to possess potent antifertility activity, anti-inflammatory activity, and to induce ovulation in anovulatory women. The crystalline compound is almost insoluble in water and has a pKa value of 2.1. Ultraviolet spectrophometric and colorimetric tests produced 98-102% recovery of added centchroman. Further studies indicated that the compound remains stable under storage conditions for 3 1/2 years, with no marked change in color and general appearance. Finally, no change in general appearance, purity, ultraviolet pattern, and assay were observed after the compound was heated at 105 degrees for 6 hours. Although the above tests involved the pure compound, additional tests with the tablet form revealed 100% stability even after 3 years of storage, again with no change in color or general appearance.     

Studies on the mode of action of ciguateric toxins

The effects of ciguatoxin, scaritoxin and maitotoxin, the main toxins involved in ciguatera fish poisoning, has been studied in pentobarbital anaesthetized cats. Intraveinous injections of increasing doses of these toxins (5 to 160 μg/kg of partially purified samples) evoked respiratory and cardiovascular disturbances: hyperventilation at low doses and respiratory depression leading to respiratory arrest at high doses; bradycardia and troubles of the atrioventricular conduction at low doses, arrhythmias and ventricular tachycardia with transient hypertension at sublethal doses, and falling arterial pressure leading to complete heart failure at high doses.The mode of action of ciguatoxin has been studied by testing the preventive efects of pharmacological compounds such as hexamethonium, atropine, propanolol and phentolamine and by proceeding to bilateral adrenalectomy. The results have indicated both central and peripheral effects. Cholinergic and also α - adrenergic actions were pointed out.     

Studies on the mode of action of hexobendine, a prospective anti-anginal drug

1. In cats anaesthetized with pentobarbitone sodium, hexobendine (0·25 mg/kg) markedly increased myocardial blood flow (measured using a heat clearance technique) and usually decreased myocardial metabolic heat production, without influencing cardiac contractility or systemic arterial blood pressure. These effects lasted for about 45 min.     

Studies on the effect of lesions of the ventral noradrenergic tract on the antinociceptive action of morphine

Benzazepine (Sch-12679) reduced the shock-induced fighting behavior of rats in a dosedependent fashion. However, the drug also impaired both locomotor behavior and rotorod performance. These results suggest that the aggression suppressive effects of Sch-12679 may be mediated by drug-induced sedation.