title: Structure-activity relationships of acetylcholinesterase noncovalent inhibitors based on a polyamine backbone. 2. Role of the substituents on the phenyl ring and nitrogen atoms of caproctamine.
abstract: Continuing our studies on polyamine-based compounds of potential interest in the field of Alzheimer's disease therapeutics, we investigated the structure-activity relationships (SAR) of a lead compound (caproctamine, 3) identified in a previous work. In particular, we varied the substituents on the phenyl ring and on the nitrogen functions (both the amine and the amide), and studied the effects of such modifications on the inhibitory potency against isolated acetyl- and butyryl-cholinesterase (AChE and BChE). Moreover, the ability of selected compounds to reverse the d-tubocurarine-induced neuromuscular blockade and their antagonism toward muscarinic M(2) receptors in guinea pig left atrium were assayed. The most interesting SAR result was the identification of a relationship between the electronic characteristics of 2-substituents (measured by pK(a)) and the AChE inhibitory potency (pIC(50)) of tertiary amine compounds 6-12, which was confirmed by the invariance of the pIC(50) values of the corresponding methiodide derivatives 14-20. With regard to the biological profile, the most interesting compound was the N-ethyl-analogue of caproctamine (9), that showed pIC(50) values of 7.73 (+/-0.02) and 5.65 (+/-0.03) against AChE and BChE, respectively. The ability to increase the acetylcholine level was maintained in the functional assay (pAI(50) for reversing the neuromuscular blockade was 6.45 (+/-0.07)), as well as the ability to antagonize the M(2) receptors (pK(b) = 5.65 (+/-0.06)). Moreover, 9 showed a long duration of action as AChE inhibitor, an useful property in view of a possible development of this compound as a therapeutic agent.
authors.affiliation: Department of Pharmaceutical Sciences, University of Bologna, Via Belmeloro 6, 40126 Bologna, Italy.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Tumiatti
authors.forename: Michela
authors.initials: M
authors.lastname: Rosini
authors.forename: Manuela
authors.initials: M
authors.lastname: Bartolini
authors.forename: Andrea
authors.initials: A
authors.lastname: Cavalli
authors.forename: Gabriella
authors.initials: G
authors.lastname: Marucci
authors.forename: Vincenza
authors.initials: V
authors.lastname: Andrisano
authors.forename: Piero
authors.initials: P
authors.lastname: Angeli
authors.forename: Rita
authors.initials: R
authors.lastname: Banzi
authors.forename: Anna
authors.initials: A
authors.lastname: Minarini
authors.forename: Maurizio
authors.initials: M
authors.lastname: Recanatini
authors.forename: Carlo
authors.initials: C
authors.lastname: Melchiorre
mesh_terms: D000110:Acetylcholinesterase / Q000737:chemistry / Q000378:metabolism*; D000577:Amides / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology; D000818:Animals; D000840:Anisoles / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology; D016275:Atrial Function / Q000187:drug effects; D002091:Butyrylcholinesterase / Q000737:chemistry; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D003964:Diaphragm / Q000294:innervation; D006168:Guinea Pigs; D006325:Heart Atria / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D008958:Models, Molecular; D018727:Muscarinic Antagonists / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D009200:Myocardial Contraction / Q000187:drug effects; D019148:Neuromuscular Blockade; D009469:Neuromuscular Junction / Q000187:drug effects / Q000502:physiology; D011073:Polyamines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D043585:Receptor, Muscarinic M2; D011976:Receptors, Muscarinic / Q000187:drug effects; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: C472794:6-(ethyl-(2-methoxybenzyl)amino)hexanoic acid (8-((6-(ethyl-(2-methoxybenzyl)amino)hexanoyl)methylamino)octyl)methylamide; D000577:Amides; D000840:Anisoles; D002800:Cholinesterase Inhibitors; D018727:Muscarinic Antagonists; D011073:Polyamines; D043585:Receptor, Muscarinic M2; D011976:Receptors, Muscarinic; C472793:caproctamine; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase