title: Synthesis and biological evaluation of new antimuscarinic compounds with amidine basic centers. A useful bioisosteric replacement of classical cationic heads.
abstract: Amidines (guanidine, formamidine, and acetamidine) were introduced as substitutes for the cationic heads present in atropine, scopolamine, and corresponding quaternary derivatives. Amidine systems are intermediate in structure between tertiary amines and quaternary compounds, at least as regards ionization and electronic properties, but differ from the latter in shape (planar not tetrahedral). They have additional binding opportunities on account of their hydrogen-bond-forming capacity. The effect of the introduction of these cationic heads on the affinity for different muscarinic acetyl choline receptor (m-AcChR) subtypes was investigated in vitro, in binding displacement studies, and in functional tests on isolated organs. All new compounds (3a,b-5a,b) showed high affinity for the m-AcChR considered, comparable or slightly inferior to that of the parent drugs (1a-e). The new amidine derivatives proved effective as spasmolytic agents, with little tendency to cause central effects. However, no separation was achieved of spasmolytic and other untoward effects, like inhibition of salivation. Thus, amidine moieties are effective bioisosteric substitutes for conventional cationic heads present in antimuscarinic agents. Their unusual physical-chemical properties make them useful tools when modulation of pharmacokinetic or pharmacodynamic effects is required.
authors.affiliation: Department of Medicinal Chemistry, Istituto De Angeli, Via Serio 15, Milan, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Cereda
authors.forename: A
authors.initials: A
authors.lastname: Ezhaya
authors.forename: M
authors.initials: M
authors.lastname: Gil Quintero
authors.forename: E
authors.initials: E
authors.lastname: Bellora
authors.forename: E
authors.initials: E
authors.lastname: Dubini
authors.forename: R
authors.initials: R
authors.lastname: Micheletti
authors.forename: A
authors.initials: A
authors.lastname: Schiavone
authors.forename: A
authors.initials: A
authors.lastname: Brambilla
authors.forename: G B
authors.initials: GB
authors.lastname: Schiavi
authors.forename: A
authors.initials: A
authors.lastname: Donetti
mesh_terms: D000578:Amidines / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D001286:Atropine Derivatives / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D002412:Cations; D002540:Cerebral Cortex / Q000378:metabolism; D055598:Chemical Phenomena; D002621:Chemistry; D002627:Chemistry, Physical; D004563:Electrochemistry; D005260:Female; D008297:Male; D015394:Molecular Structure; D009116:Muscarine / Q000037:antagonists & inhibitors*; D009119:Muscle Contraction / Q000187:drug effects; D009206:Myocardium / Q000378:metabolism; D010276:Parasympatholytics / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D011976:Receptors, Muscarinic / Q000378:metabolism; D012472:Salivation / Q000187:drug effects; D012602:Scopolamine Derivatives / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D013363:Submandibular Gland / Q000378:metabolism
chemical_list: D000578:Amidines; D001286:Atropine Derivatives; D002412:Cations; D010276:Parasympatholytics; D011976:Receptors, Muscarinic; D012602:Scopolamine Derivatives; D009116:Muscarine