3-iodothyronamine (T1AM), a novel antagonist of muscarinic receptors.
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 (10nM-100μM) was able to i) displace [3H]-NMS (0.20nM) binding to membrane preparations from CHO cells stably transfected with human muscarinic receptor subtypes (M1-M5); ii) modify basal or acetylcholine induced pERK1/2levels 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 pERK1/2levels. 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.
Dept. of NEUROFARBA, Section of Pharmacology, University of Florence, 50139 Florence, Italy.
Annunziatina
A
Laurino
Dept. of NEUROFARBA, Section of Pharmacology, University of Florence, 50139 Florence, Italy.
Rosanna
R
Matucci
Dept. of Pharmaceutical Science, University of Milan, 20100 Milan, Italy.
Giulio
G
Vistoli
Dept. of NEUROFARBA, Section of Pharmacology, University of Florence, 50139 Florence, Italy. Electronic address: laura.raimondi@unifi.it.
Laura
L
Raimondi
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D002217:Carbachol / Q000494:pharmacology; D020134:Catalytic Domain; D006224:Cricetinae; D006801:Humans; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D062105:Molecular Docking Simulation; D018727:Muscarinic Antagonists / Q000378:metabolism / Q000494:pharmacology*; D009119:Muscle Contraction / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D043587:Receptor, Muscarinic M3 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D013970:Thyronines / Q000378:metabolism / Q000494:pharmacology*; D001743:Urinary Bladder / Q000187:drug effects / Q000502:physiology
C487948:3-iodothyronamine; D018727:Muscarinic Antagonists; D043587:Receptor, Muscarinic M3; D013970:Thyronines; D002217:Carbachol; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D000109:Acetylcholine
3-iodothyroacetic acid; 3-iodothyrothyronamine; Muscarinic receptors; Thyroid