Iodinated 2-aminotetralins and 3-amino-1-benzopyrans: ligands for dopamine D2 and D3 receptors

In developing selective ligands for dopamine D2 and D3 receptors, several iodinated 2-aminotetralins and 3-amino-1-benzopyrans, trans-7-hydroxy-2-[N-(3'-iodo-2'- propenyl)amino]tetralin (1), trans-monohydroxy-2-[N-propyl-N-(3'-iodo-2'-propenyl)amino]tetralin (7-, 5-, and 6-OH-PIPAT) (2, 3, and 4), and trans-monohydroxy-3,4-dihydro-3-[N-propyl-N-(3'-iodo-2'- propenyl)-amino]-2H-1-benzopyran (6- and 8-OH-benzopyrans) (5 and 6), were prepared. These compounds were evaluated for their binding profiles in several membrane preparations: Spodoptera frugiperda (Sf9) cells expressing dopamine D2 (non-GTP coupled, low-affinity states) and D3 receptors, HEK293 cells expressing dopamine D2 receptors in high-affinity states (D2H), rat hippocampal homogenates for 5-HT1A receptors, and cerebellar homogenates for sigma receptors. The mono-N-alkylated 2-aminotetralin, 1, displayed high sigma binding (Ki = 1.68 nM) with a moderate D3 binding (Ki = 30.2 nM). Derivatives with one N-propyl and one N-(3'-iodo-2'-propeny) group generally displayed high to moderate affinity to D3 receptors (Ki = 2.90, 1.85, 0.99, 2.20, 31.4, and 6.69 nM for 7-OH-DPAT [7-hydroxy-2-(N,N-di-n-propylamino)tetralin], 2, 3, 4, 5, and 6, respectively). It is interesting to note that all of the active D3 ligands also displayed comparable binding to the high affinity states of D2 receptors in HEK293 cells (Ki = 6.6, 3.6, 9.7, and 10.8 nM for 2, 3, 4, and 6, respectively). Among all of the tetralin derivatives tested, 5-OH-PIPAT, 3, showed the highest binding affinity to D3 receptors (Ki = 0.99 nM) and better selectivity (KiD2H/KiD3, KiD2/KiD3, Ki5-HT1A/KiD3 and Ki sigma/KiD3 = 3.64, 327, 48.4, and 1250 nM, respectively), making it the best ligand for studying dopamine D2H and D3 receptors.