ABSTRACT
(exo, exo)-2-Aryltropane-3-carboxylic esters of types 6, 7, and 10 lower circulating blood glucose levels by 60--80%. This activity is accompanied by an analgesic activity roughly equal to that of codeine. Both of these activities reside in the 1R enantiomer and extensive structure-activity studies failed to separate them. The specific opioid antagonist nalorphine blocks the analgesic activity but does not diminish the hypoglycemic action. Conformational integrity afforded by the ethylene bridge is neccessary for the observed activities.
Subject(s)
Analgesics, Opioid/chemical synthesis , Hypoglycemic Agents/chemical synthesis , Tropanes/chemical synthesis , Administration, Oral , Animals , Catalepsy/chemically induced , Dealkylation , Dogs , Humans , Hypoglycemic Agents/administration & dosage , Injections, Subcutaneous , Male , Mice , Molecular Conformation , Rats , Respiratory Insufficiency/chemically induced , Stereoisomerism , Structure-Activity Relationship , Tropanes/administration & dosage , Tropanes/pharmacologyABSTRACT
Ethylenediamine tetraacetic acid (EDTA) was used as a nociceptive stimulus intradermally in the guinea pig. The responses evoked by EDTA included vocalization, biting and scratching at the site of injection and escape behavior. Nociception by EDTA was shown to be the result of its cation chelating activity. The suppression of EDTA-induced responses proved to be a rapid and effective antinociceptive test. The narcotic analgesics morphine, codeine, meperidine and methadone and the narcotic antagonist analgesics cyclazocine, cyclorphan, nalorphine and pentazocine were active. The slopes of the dose-response curves of the narcotic antagonist analgesics were significantly shallower than those of the narcotic analgesics. The test was highly specific for these analgesics. Antipyretic analgesics and various nonanalgesic drugs were inactive.
Subject(s)
Analgesics, Opioid/pharmacology , Narcotic Antagonists/pharmacology , Narcotics/pharmacology , Pain/physiopathology , Analgesics/pharmacology , Animals , Behavior, Animal/drug effects , Edetic Acid/administration & dosage , Edetic Acid/pharmacology , Guinea Pigs , Injections, Subcutaneous , Male , Models, Biological , Time FactorsABSTRACT
Various nitrogen analogs of delta6a,10a-tetrahydrocannabinol were synthesized by a general procedure described in an earlier communication. Minimum effective doses (MED50's) and lethal doses (LD50's) were determined by a modified Irwin mouse screen after iv administration of compounds in PEG 200. The most potent compounds were the propargyl (5t), allyl (5m), and chloroallyl (5o-q) derivatives. Overt behavioral effects (CNS depression, static ataxia, and hypersensitivity) of 5t and Roger Adams' carbocyclic analog (III) were found to be similar in the mouse, cat, dog, and monkey. Dichloroisoproterenol prevented and reversed many of the depressant effects of both III and 5t but had no effect on the ataxia produced by these compounds. In antinociceptive tests, 5t was active in the phenylquinone and Eddy hot-plate tests but was inactive in the tail-flick test.
Subject(s)
Benzopyrans/chemical synthesis , Cannabis/chemical synthesis , Dronabinol/chemical synthesis , Pyridines/chemical synthesis , Pyrroles/chemical synthesis , Animals , Behavior, Animal/drug effects , Benzopyrans/pharmacology , Benzopyrans/toxicity , Cats , Dogs , Dronabinol/analogs & derivatives , Dronabinol/pharmacology , Haplorhini , Humans , Lethal Dose 50 , Mice , Morphine Dependence/physiopathology , Motor Activity/drug effects , Nictitating Membrane/drug effects , Pyridines/pharmacology , Pyridines/toxicity , Pyrroles/pharmacology , Pyrroles/toxicity , Reflex/drug effects , Structure-Activity RelationshipABSTRACT
Norapomorphine and ten of its N-substituted derivatives were prepared by modifications of procedures described earlier. In a dog emesis test the N-ethyl and N-n-propyl compounds had minimum effective doses of 0.00025 and 0.0005 mg/kg, respectively, when administered iv, sc, or im. In a modified Irwin mouse profile screen the minimum effective iv dose was 0.013 mg/kg for the N-ethyl and 0.0024 mg/kg for the N-n-propyl compound; percutaneous absorption was also observed in mice. All compounds examined caused the stereotyped apomorphine behavior syndrome but hypotensive effects were not serious.
