title: Structure-activity relationships of methoctramine-related polyamines as muscarinic antagonist: effect of replacing the inner polymethylene chain with cyclic moieties.
abstract: The aim of the present paper was to investigate the role of the octamethylene spacer of methoctramine (1) on the biological profile. Thus, this spacer was incorporated into a dianiline or dipiperidine moiety to determine whether flexibility and the basicity of the inner nitrogen atoms are important determinants of potency with respect to muscarinic receptors. The most potent compound was 4, which displayed, in the functional assays, a comparable potency at muscarinic M(2) receptors with respect to 1, and, in the binding assays, a loss of potency and selectivity toward muscarinic M(1) and M(3) receptor subtypes. Both compounds were endowed with antinociceptive activity. Furthermore, in microdialysis tests in rat parietal cortex, they enhanced acetylcholine release, most likely by antagonizing presynaptic muscarinic receptor subtypes.
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Università di Bologna, Via Belmeloro 6, 40126 Bologna, Italy. vincenzo.tumiatti@unibo.it
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Tumiatti
authors.forename: Anna
authors.initials: A
authors.lastname: Minarini
authors.forename: Andrea
authors.initials: A
authors.lastname: Milelli
authors.forename: Michela
authors.initials: M
authors.lastname: Rosini
authors.forename: Michela
authors.initials: M
authors.lastname: Buccioni
authors.forename: Gabriella
authors.initials: G
authors.lastname: Marucci
authors.forename: Carla
authors.initials: C
authors.lastname: Ghelardini
authors.forename: Cristina
authors.initials: C
authors.lastname: Bellucci
authors.forename: Carlo
authors.initials: C
authors.lastname: Melchiorre
mesh_terms: D000109:Acetylcholine / Q000378:metabolism; D000110:Acetylcholinesterase / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D002091:Butyrylcholinesterase / Q000737:chemistry / Q000378:metabolism; D016466:CHO Cells / Q000187:drug effects; D002540:Cerebral Cortex / Q000187:drug effects; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006224:Cricetinae; D003412:Cricetulus; D003959:Diamines / Q000737:chemistry*; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D006168:Guinea Pigs; D006325:Heart Atria / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007082:Ileum / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D015394:Molecular Structure; D018727:Muscarinic Antagonists / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism; D010296:Parietal Lobe / Q000187:drug effects; D019920:Photoaffinity Labels; D011073:Polyamines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011817:Rabbits; D011869:Radioligand Assay; D051381:Rats; D011976:Receptors, Muscarinic / Q000145:classification / Q000187:drug effects; D013329:Structure-Activity Relationship; D014649:Vas Deferens / Q000187:drug effects / Q000378:metabolism
chemical_list: D002800:Cholinesterase Inhibitors; D003959:Diamines; D018727:Muscarinic Antagonists; D019920:Photoaffinity Labels; D011073:Polyamines; D011976:Receptors, Muscarinic; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase; D000109:Acetylcholine; C054938:methoctramine