Preparation and biological effects of pure stereoisomeric novel soft anticholinergics.
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.
Tóth-Sarudy
E
E
IVAX Drug Research Institute Ltd., Budapest, Hungary.
Tóth
G
G
Pallagi
I
I
Seres
G
G
Vitális
B
B
Tapfer
M
M
Perczel
V
V
Kurucz
I
I
Bodor
N
N
Zubovics
Z
Z
D000818:Animals; D001919:Bradycardia / Q000139:chemically induced / Q000188:drug therapy; D002217:Carbachol; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D018680:Cholinergic Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D002855:Chromatography, Thin Layer; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects; D066298:In Vitro Techniques; D007202:Indicators and Reagents; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D018721:Muscarinic Agonists; D018727:Muscarinic Antagonists / Q000494:pharmacology; D009130:Muscle, Smooth / Q000187:drug effects; D011813:Quinuclidinyl Benzilate / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011976:Receptors, Muscarinic / Q000187:drug effects / Q000378:metabolism; D013056:Spectrophotometry, Ultraviolet; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014132:Trachea / Q000187:drug effects
D018680:Cholinergic Antagonists; D007202:Indicators and Reagents; D018721:Muscarinic Agonists; D018727:Muscarinic Antagonists; D011976:Receptors, Muscarinic; D011813:Quinuclidinyl Benzilate; D002217:Carbachol