3-iodothyronamine (T1AM) is a trace amine suspected to derive from thyroid hormone metabolism. T1AM was described as a ligand of G-protein coupled monoaminergic receptors, including trace amine associated receptors, suggesting the amine may exert a modulatory role on the monoaminergic transmission. Nothing is known on the possibility that T1AM could also modulate the cholinergic transmission interacting with muscarinic receptors. We evaluated whether T1AM (10 nM–100 μM) was able to i) displace [3H]-NMS (0.20 nM) binding to membrane preparations from CHO cells stably transfected with human muscarinic receptor subtypes (M1-M5); ii) modify basal or acetylcholine induced pERK1/2 levels in CHO expressing the human muscarinic type 3 receptor subtype by Western blot iii) modify basal and carbachol-induced contraction of isolated rat urinary bladder. T1AM fitting within rat muscarinic type 3 receptor was simulated by Docking studies. T1AM recognized all muscarinic receptor subtypes (pKi values in the micromolar range). Interacting at type 3, T1AM reduced acetylcholine-increased pERK1/2 levels. T1AM reduced carbachol-induced contraction of the rat urinary bladder. The fenoxyl residue and the iodide ion were found essential for establishing contacts with the active site of the rat muscarinic type 3 receptor subtype. Our results indicate that T1AM binds at muscarinic receptors behaving as a weak, not selective, antagonist. This finding adds knowledge on the pharmacodynamics features of T1AM and it may prompt investigation on novel pharmacological effects of T1AM at conditions of hyper-activation of the muscarinic tone including the overactive urinary bladder.
|Titolo:||3-iodothyronamine (T1AM), a novel antagonist of muscarinic receptors|
VISTOLI, GIULIO (Penultimo)
|Parole Chiave:||3-iodothyroacetic acid; 3-iodothyrothyronamine; Muscarinic receptors; Thyroid; Acetylcholine; Animals; Carbachol; Catalytic Domain; Cricetinae; Humans; Male; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Molecular Docking Simulation; Muscarinic Antagonists; Muscle Contraction; Phosphorylation; Rats; Receptor, Muscarinic M3; Thyronines; Urinary Bladder; Pharmacology|
|Settore Scientifico Disciplinare:||Settore CHIM/08 - Chimica Farmaceutica|
|Data di pubblicazione:||2016|
|Digital Object Identifier (DOI):||10.1016/j.ejphar.2016.10.027|
|Appare nelle tipologie:||01 - Articolo su periodico|