ABSTRACT
A series of Mannich bases and aminomethyl derivatives of ethyl [2,3-dichloro-4-(4-hydroxybenzoyl)phenoxy]acetate were synthesized and tested for saluretic and diuretic activities. The effects of nitrogen and aromatic nuclear substitution, reorientation of the aminomethyl group relative to that of the phenolic hydroxyl group, and replacement of either the phenolic hydroxyl or the aminomethyl group by other functional groups are described. Ethyl [2,3-dichloro-4-[3-(aminomethyl)-4-hydroxybenzoyl]phenoxy]acetate (27) was found to be a very potent, high-ceiling diuretic.
Subject(s)
Diuretics/chemical synthesis , Glycolates/chemical synthesis , Administration, Oral , Animals , Biological Assay , Blood Pressure/drug effects , Dogs , Drug Evaluation, Preclinical , Female , Furosemide/pharmacology , Glomerular Filtration Rate/drug effects , Glycolates/administration & dosage , Glycolates/pharmacology , Indicators and Reagents , Macaca fascicularis , Male , Methylamines/administration & dosage , Methylamines/chemical synthesis , Methylamines/pharmacology , Rats , Rats, Inbred SHR , Sodium/urine , Structure-Activity RelationshipABSTRACT
A series of substituted 5,6-dihydrofuro[3,2-f]-1,2-benzisoxazoles was prepared and evaluated for their saluretic and uricosuric properties. Pharmacological evaluation of the title compounds was carried out in mice, rats, dogs, and monkeys. The diuretic/saluretic nature of these compounds was observed in all species, whereas the uricosuric activity was best seen in the Cebus monkey. Evaluation of the enantiomers of 8-chloro-3-(o-fluorophenyl)-5,6-dihydrofuro [3,2-f]-1,2-benzisoxazole-6-carboxylic acid (15k) revealed that only the (+) enantiomer (29) displayed diuretic and saluretic activity, whereas both enantiomers possessed uricosuric activity. X-ray analysis showed that the (-) enantiomer (30) possesses the 2R configuration.
Subject(s)
Diuretics/chemical synthesis , Furans/chemical synthesis , Isoxazoles/chemical synthesis , Oxazoles/chemical synthesis , Uricosuric Agents/chemical synthesis , Animals , Chlorides/urine , Dogs , Dose-Response Relationship, Drug , Furans/pharmacology , Haplorhini , Isoxazoles/pharmacology , Mice , Models, Molecular , Natriuresis/drug effects , Potassium/urine , Rats , Sodium/urine , Stereoisomerism , Structure-Activity RelationshipABSTRACT
Various basic esters of nitrogen (2) and carbocyclic (3 and 4) analogs of cannabinoids were synthesized using dicyclohexylcarbodiimide in methylene chloride. The compounds in the three series werw studied in selected pharmacological tests in mice, rats, dogs, and cats. It was shown that making the basic ester from the phenol retains biological activity and can lead to a greater selectivity of action, particularly the antinociceptive activity. The most interesting esters were 5, 6, 10, and 14 in the nitrogen analogs series and 19 and 20 in the carbocyclic series. Compound 5 was more potent than codeine in the writhing, hot-plate, and tail-flick tests and is at present undergoing clinical testing. Compound 20 was very potent in the mouse audiogenic seizure test and is of interest as an anticovulsant agent.
Subject(s)
Cannabis/chemical synthesis , Dronabinol/chemical synthesis , Acoustic Stimulation , Aggression/drug effects , Analgesics , Animals , Ataxia/chemically induced , Behavior, Animal/drug effects , Cats , Dihydroxyphenylalanine/pharmacology , Dogs , Dronabinol/analogs & derivatives , Dronabinol/pharmacology , Dronabinol/toxicity , Esters , Haplorhini , Humans , Hypnotics and Sedatives , Lethal Dose 50 , Male , Mice , Motor Activity/drug effects , Phytotherapy , Rats , Reaction Time/drug effects , Seizures/etiology , Sleep/drug effects , Structure-Activity RelationshipABSTRACT
Various CNS-active cannabinoids in which the alicyclic ring was thiopheno, cyclopenteno, or cyclohexeno with the alkyl substituent in various positions (structural types 1-6) were synthesized by procedures described previously. These compounds were compared in selected pharmacological tests in mice, rats, dogs, and cats. The results suggested that methyl substitution in the close proximity of the phenolic hydroxyl group strongly influenced the activity of some cannabinoids, particularly of those which had a planar five-membered alicyclic ring rather than a six-membered ring.
