Synthesis and Biological Evaluation of Metabolites of 2‑<i>n</i>‑Butyl-9-methyl-8-[1,2,3]triazol-2-yl‑9<i>H</i>‑purin-6-ylamine (ST1535), A Potent Antagonist of the A_2A Adenosine Receptor for the Treatment of Parkinson’s Disease

The synthesis and preliminary in vitro evaluation of five metabolites of the A_2A antagonist ST1535 (<b>1</b>) are reported. The metabolites, originating in vivo from enzymatic oxidation of the 2-butyl group of the parent compound, were synthesized from 6-chloro-2-iodo-9-methyl-9<i>H</i>-purine (<b>2</b>) by selective C–C bond formation via halogen/magnesium exchange reaction and/or palladium-catalyzed reactions. The metabolites behaved in vitro as antagonist ligands of cloned human A_2A receptor with affinities (<i>K</i>_i 7.5–53 nM) comparable to that of compound <b>1</b> (<i>K</i>_i 10.7 nM), thus showing that the long duration of action of <b>1</b> could be in part due to its metabolites. General behavior after oral administration in mice was also analyzed

Highly Potent and Selective MT₂ Melatonin Receptor Full Agonists from Conformational Analysis of 1‑Benzyl-2-acylaminomethyl-tetrahydroquinolines

Molecular superposition models guided the design of novel melatonin receptor ligands characterized by a 2-acylaminomethyltetrahydroquinoline scaffold. Starting from the structure of <i>N</i>-anilinoethylamide ligands, the flexible chain was conformationally constrained to reproduce the bioactive conformation of melatonin. Structure–activity relationships were investigated, focusing on the substituent at the nitrogen atom, the position of the methoxy group, and the replacement of the amide side chain by urea and thiourea groups. The compounds were tested for binding affinity and intrinsic activity at human MT₁ and MT₂ receptors. Structural optimization resulted in <i>N</i>-[(1-benzyl-1,2,3,4-tetrahydro-5-methoxyquinolin-2-yl)­methyl]­propionamide (UCM1014), with picomolar MT₂ binding affinity (<i>K</i>_i = 0.001 nM), more than 10000-fold selectivity over the MT₁ receptor, and a full agonist profile (GTPγS test), being the most potent MT₂-selective full agonist reported to date. Molecular dynamics simulations provided a rationale for high binding affinity, stereoselectivity, and agonist behavior of these novel melatonin receptor ligands based on superposition models and conformational preference