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 (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.