ABSTRACT
A series of pure stereoisomeric soft glycopyrrolate analogues 3, 4 and 5 was synthesized using chiral intermediates and by careful separation of the stereoisomers formed during the last quaternization step of the synthesis. The stereochemistry of the products was elucidated using various 1D and 2D NMR techniques. Anticholinergic activity of the new compounds was determined by receptor binding studies and performing tests on isolated organs and by in vivo tests. Receptor binding revealed that in the higher alkyl ester series the (2R, 1'R, 3'R) and the (2R, 1'S, 3'S) isomers were the compounds showing the highest receptor affinity furthermore it demonstrated the confines of the length of the alkyl chain. In vitro isolated organ experiments correlated well with the receptor binding results, and in vivo investigations indicated the soft character of the compounds.
Subject(s)
Cholinergic Antagonists/chemical synthesis , Cholinergic Antagonists/pharmacology , Animals , Bradycardia/chemically induced , Bradycardia/drug therapy , Carbachol , Cerebral Cortex/drug effects , Cerebral Cortex/metabolism , Cholinergic Antagonists/chemistry , Chromatography, Thin Layer , Guinea Pigs , Ileum/drug effects , In Vitro Techniques , Indicators and Reagents , Magnetic Resonance Spectroscopy , Male , Muscarinic Agonists , Muscarinic Antagonists/pharmacology , Muscle, Smooth/drug effects , Quinuclidinyl Benzilate/pharmacology , Rats , Rats, Sprague-Dawley , Receptors, Muscarinic/drug effects , Receptors, Muscarinic/metabolism , Spectrophotometry, Ultraviolet , Stereoisomerism , Structure-Activity Relationship , Trachea/drug effectsSubject(s)
Memory/drug effects , Thiazoles/pharmacology , Animals , Avoidance Learning/drug effects , Mice , Quinuclidinyl Benzilate , Radioligand Assay , RatsSubject(s)
Antipsychotic Agents/pharmacology , Fluphenazine/analogs & derivatives , Animals , Antipsychotic Agents/pharmacokinetics , Avoidance Learning/drug effects , Behavior, Animal/drug effects , Dogs , Fluphenazine/pharmacokinetics , Fluphenazine/pharmacology , Hemodynamics/drug effects , Radioimmunoassay , RatsABSTRACT
gamma-Endorphin inhibits the amphetamine-induced stereotypy in rats with an approximate ED50 of 0.3 mg/kg. SC. The anti-amphetamine effect of gamma-endorphin can be antagonized to a certain extent by both the dopamine receptor stimulant 2-bromo-ergocryptine and the opiate receptor antagonist naloxone.
