The design of novel methoctramine-related tetraamines as muscarinic receptor subtype selective antagonists.
Several novel methoctramine-related tetraamines were designed, and their biological profiles at muscarinic receptor subtypes were assessed by functional experiments in isolated guinea pig and rat atria (M2) and smooth muscle (ileum and trachea, M3) and by binding assays in rat cortex (M1), heart (M2), and submaxillary gland (M3) homogenates and NG 108-15 cells (M4). Tripitramine, a nonsymmetrical tetraamine, resulted in the most potent and the most selective muscarinic M2 receptor antagonist of the series (pA2 = 9.14-9.85; pKi = 9.54). Spirotramine (FC 15-94), a symmetrical tetraamine, was able to differentiate between muscarinic M1 receptors (pKi = 7.88) and the other subtypes (M2, pKi = 6.20; M3, pKi = 5.81; M4, pKi = 6.27). Thus, tripitramine and spirotramine could be valuable tools for the pharmacological classification and characterization of muscarinic receptor subtypes.
Melchiorre
C
C
Department of Pharmaceutical Sciences, University of Bologna, Italy.
Minarini
A
A
Budriesi
R
R
Chiarini
A
A
Spampinato
S
S
Tumiatti
V
V
D000818:Animals; D016275:Atrial Function; D001569:Benzodiazepines / Q000494:pharmacology; D001570:Benzodiazepinones / Q000494:pharmacology; D003959:Diamines / Q000737:chemistry / Q000494:pharmacology*; D015195:Drug Design; D006168:Guinea Pigs; D006325:Heart Atria / Q000187:drug effects; D007082:Ileum / Q000187:drug effects / Q000502:physiology; D018727:Muscarinic Antagonists / Q000737:chemistry / Q000494:pharmacology*; D009119:Muscle Contraction / Q000187:drug effects / Q000502:physiology; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D010276:Parasympatholytics / Q000737:chemistry / Q000494:pharmacology*; D010880:Piperidines / Q000494:pharmacology; D010890:Pirenzepine / Q000494:pharmacology; D051381:Rats; D011976:Receptors, Muscarinic / Q000145:classification / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013363:Submandibular Gland / Q000187:drug effects / Q000378:metabolism; D014132:Trachea / Q000187:drug effects / Q000378:metabolism
D001570:Benzodiazepinones; D003959:Diamines; D018727:Muscarinic Antagonists; D010276:Parasympatholytics; D010880:Piperidines; D011976:Receptors, Muscarinic; C069054:AQ-RA 741; D001569:Benzodiazepines; C084480:tripitramine; D010890:Pirenzepine; C054938:methoctramine