ABSTRACT
A variety of tropane derivatives 14a-g were prepared via the reaction of the alcohol analogs 12a and 12b with substituted fluorobenzenes 13a-f. The prepared compounds were tested for their activity and selectivity toward the norepinephrine transporter (NET) and serotonin transporter (SERT) using yohimbine-induced mortality and 5-hydroxytryptophan-induced neurotoxicity in mice, respectively. All the tested compounds were found to be NE and 5-HT reuptake inhibitors except 14d which exhibited selective 5-HT reuptake inhibition activity.
Subject(s)
Norepinephrine Plasma Membrane Transport Proteins/metabolism , Norepinephrine/pharmacology , Selective Serotonin Reuptake Inhibitors/chemical synthesis , Serotonin Plasma Membrane Transport Proteins/metabolism , Serotonin/pharmacology , Tropanes/chemical synthesis , 5-Hydroxytryptophan/toxicity , Adrenergic alpha-Antagonists/toxicity , Animals , Citalopram/chemical synthesis , Citalopram/chemistry , Clomipramine/chemical synthesis , Clomipramine/chemistry , Crystallography, X-Ray , Dose-Response Relationship, Drug , Drug Evaluation, Preclinical , Fluoxetine/chemical synthesis , Fluoxetine/chemistry , Mice , Molecular Structure , Norepinephrine Plasma Membrane Transport Proteins/drug effects , Serotonin Plasma Membrane Transport Proteins/drug effects , Selective Serotonin Reuptake Inhibitors/pharmacology , Tropanes/chemistry , Tropanes/pharmacology , Yohimbine/antagonists & inhibitors , Yohimbine/toxicityABSTRACT
In this investigation, the water-soluble drugs nitenpyram and clomipramine HCl were encapsulated using coacervation, solvent evaporation and film-coating. The effect of different process factors on the encapsulation efficiency and the release profile of the microparticles was evaluated. For coacervation it was shown that the core to wall ratio was the most important factor. For solvent evaporation using an w/o emulsion the type and concentration of the surfactant were the most important parameters for a successful encapsulation. Additionally the coated material was tested for its stability under different conditions as a powder or compressed into tablets. It could clearly be demonstrated that the coated drug substance exhibited a better stability then the uncoated material. The particles prepared by film-coating showed the best stability.
Subject(s)
Clomipramine/chemical synthesis , Pyridines/chemical synthesis , Water/chemistry , Clomipramine/pharmacokinetics , Drug Compounding/methods , Neonicotinoids , Pyridines/pharmacokinetics , SolubilityABSTRACT
Ten new 3,5-diphenyl-2-pyrazoline derivatives were synthesised by reacting 1,3-diphenyl-2-propen-1-one with hydrazine hydrate. The chemical structures of the compounds were proved by means of their IR, 1H-NMR spectroscopic data and microanalyses. The antidepressant activities of these compounds were evaluated by the 'Porsolt Behavioural Despair Test' on Swiss-Webster mice. 3-(4-Methoxyphenyl)-5-(3,4-dimethoxyphenyl)-2-pyrazoline, 3-(4-methoxyphenyl)-5-(2-chloro-3,4-dimethoxyphenyl)-2-pyrazoline and 3-(4-chlorophenyl)-5-(2-chloro-3,4-dimethoxyphenyl)-2-pyrazoline reduced 41.94-48.62% immobility times at 100 mgkg(-1) dose level. In addition, it was found that 4-methoxy and 4-chloro substituents on the phenyl ring at position 3 of the pyrazoline ring increased the antidepressant activity; the replacement of these groups by bromo and methyl substituents decreased activity in mice.
Subject(s)
Antidepressive Agents/chemical synthesis , Antidepressive Agents/pharmacology , Pyrazoles/chemical synthesis , Pyrazoles/pharmacology , Animals , Clomipramine/chemical synthesis , Clomipramine/chemistry , Clomipramine/pharmacology , Dose-Response Relationship, Drug , Drug Design , Drug Evaluation, Preclinical , Magnetic Resonance Spectroscopy , Male , Mice , Neuropsychological Tests , Pyrazoles/chemistry , Spectrophotometry, Infrared , Structure-Activity Relationship , Swimming , Tranylcypromine/chemical synthesis , Tranylcypromine/chemistry , Tranylcypromine/pharmacologyABSTRACT
To quantitatively determine tricyclic antidepressant agents, we used a combined gas chromatograph/mass spectrometer system, and deuterium-labeled internal standards. Recovery exceeds 95% and the coefficient of variation is less than 4% for human whole-blood samples supplemented with 5 to 15 ng of clomipramine hydrochloride or 20 to 60 ng of dehydroimipramine hydrogen fumarate per milliliter. For both amines, the detection limit is 0.3 mug/liter; Six healthy volunteers who received a single oral dose of 50 mg of clomipramine hydrochloride showed peak drug concentrations in the blood 3 to 5 h after administration, ranging between 14.4 and 30.1 mug/liter. Plasma/whole blood concentration ratios varied from 0.70 to 1.20, and the cumulative renal elimination from 0 to 72 h is less than 0.2% of the dose. This method is suitable for in vivo bioavailability studies of unchanged clomipramine, dehydroimipramine, and imipramine after a single oral dose of as little as 25 mg.
