Subject(s)
Diabetes Mellitus/etiology , Diabetic Nephropathies/complications , Diabetic Nephropathies/etiology , Graft Rejection/etiology , Kidney Transplantation/adverse effects , Biopsy , Diabetic Nephropathies/pathology , Female , Humans , Kidney/pathology , Male , Middle Aged , Sclerosis , Time Factors , Transplantation, HomologousABSTRACT
3,5-Dimethylbenzo[1,2-c:5,4-c']dipyrazoles, optionally substituted in the 1-, 7-, and 8-positions, were synthesized from resorcinols. These compounds display affinity for adenosine A1 (rat brain) and A2 (human platelet) receptors. In addition, these compounds reverse contractions of guinea pig tracheal cylindrical segments induced by potassium chloride, histamine, acetylcholine, and 5-hydroxytryptamine, as well as reverse bronchospasm induced by aerosolized histamine in the conscious guinea pig.
Subject(s)
Adenosine/antagonists & inhibitors , Pyrazoles/pharmacology , Animals , Bronchi/drug effects , Guinea Pigs , Humans , Muscle Contraction/drug effects , Rats , Receptors, Purinergic/metabolism , Structure-Activity RelationshipABSTRACT
A number of N,N'-dialkylarylamidines were synthesized and evaluated for antidepressant activity. Several of these compounds were synthesized from the corresponding nitriles by a new method. Slight structural modification in the series caused a marked change in biological activity and led to compounds as active as imipramine. The arylacetamidine, N,N'-dimethyl-2-naphthaleneethanimidamide hydrochloride (33) (napactadine) was selected for clinical study. Forty-eight additional analogues of 33, including a number of N-alkylamidines, were prepared.
Subject(s)
Amidines/therapeutic use , Depression/drug therapy , Aggression/drug effects , Amidines/chemical synthesis , Amidines/pharmacology , Animals , Blepharoptosis/chemically induced , Cerebral Cortex/drug effects , Cerebral Cortex/metabolism , Chemical Phenomena , Chemistry , Drug Evaluation , Drug Synergism , Electric Stimulation , Male , Mice , Norepinephrine/metabolism , Rats , Reserpine/antagonists & inhibitors , Structure-Activity Relationship , Yohimbine/pharmacologySubject(s)
Acetophenones/pharmacology , Appetite Depressants , Imidazoles/pharmacology , Acetophenones/administration & dosage , Acetophenones/toxicity , Animals , Body Weight/drug effects , Cats , Dextroamphetamine/pharmacology , Diethylpropion/pharmacology , Dogs , Drug Evaluation, Preclinical , Eating/drug effects , Female , Hemodynamics/drug effects , Imidazoles/administration & dosage , Imidazoles/toxicity , Lethal Dose 50 , Male , Mice , Mice, Inbred ICR , Motor Activity/drug effects , Rats , Species Specificity , Time FactorsABSTRACT
The effects of d,1-alpha-methyltyrosine (alphaMT), haloperidol, phenoxybenazmine, propranolol, methysergide and cyproheptadine on the anorexigenic activities of DITA and d-amphetamine were studied in male mice. The pretreatment of mice with methysergide (10 mg/kg, s.c.), cyproheptadine (5 mg/kg, i.p.), phenoxybenzamine (10 mg/kg, i.p.), and propranolol (5 mg/kg, i.p.) failed to alter the anorexigenic effect of DITA and d-amphetamine. On the other hand, alphaMT (32 mg/kg, i.p.) and haloperidol (0.5 mg/kg, i.p.) significantly antagonized the anorexigenic effect of DITA and d-amphetamine. Our data indicate that the anorexigenic activities of DITA and d-amphetamine are mediated mainly through the dopaminergic system.
Subject(s)
Acetophenones/pharmacology , Appetite Depressants/pharmacology , Dextroamphetamine/pharmacology , Dopamine/metabolism , Eating/drug effects , Imidazoles/pharmacology , Acetophenones/antagonists & inhibitors , Animals , Appetite Depressants/antagonists & inhibitors , Cyproheptadine/pharmacology , Dextroamphetamine/antagonists & inhibitors , Haloperidol/pharmacology , Imidazoles/antagonists & inhibitors , Male , Methyltyrosines/pharmacology , Methysergide/pharmacology , Mice , Phenoxybenzamine/pharmacology , Propranolol/pharmacologyABSTRACT
The effect of DL-alpha methyltyrosine (alpha-MT), 6-hydroxydopa (6-OH DOPA), haloperidol, phenoxybenzamine and propranolol on the stimulant activity of the anorexigenic agents (3',4'-dichloro-2-(2-imidazolin-2-yl-thio)-acetophenone HBr) (DITA) and d-amphetamine was studied in male mice. The pretreatment of mice with alpha-MT, (32, 64 mg/kg i.p.), significantly reduced the increase in motor activity induced by DITA or d-amphetamine. On the other hand, pretreatment of mice with 6-OH DOPA, (100, 150 mg/kg, i.v.), did not significantly after the stimulant effect of either DITA or d-amphetamine. In the case of haloperidol, it significantly reduced the increase of motor activity induced by DITA or d-amphetamine; propranolol and phenoxybenzamine were ineffective. Our results support the hypothesis that the stimulant effect of DITA and d-amphetamine depends mainly on the integrity of the central dopaminergic rather than the noradrenergic system.
