D1-like receptors distinguishing thieno-azecine regioisomers

Abstract

Designing ligands with D₁/D₅ subtype selectivity is a challenge because of the high identity within the receptor helices. Based on the lead compounds 1–3, the thieno-benzazecine regioisomers 4 and 5 were synthesized and biologically evaluated for their affinity towards the five dopamine receptor subtypes utilizing a radioligand binding affinity technique. Within the D₁-like family, compound 4 showed 20 fold selectivity for the D₅ subtype over D₁ subtype (K_i = 3 nM, D₁: 60 nM), while its regioisomer, compound 5 with a reversed thiophene position, prefers the D₁ subtype over the D₅ subtype (K_i = 4 nM, D₅: 15 nM). The benzothieno-benzazecine analog 6 was shown to be one of the few azecine derivatives with high affinity for both the D₁- and the D₂-like family members in the same order of magnitude (K_i = 1.5 nM for D₂ and 1.9 nM for D₅). Thorough analysis of the amino acid residues constituting the binding pockets of the target dopamine receptor subtypes revealed that at the D₅ receptor, either serine S 6.62 and threonine T 7.33 residues or a water network, stabilized by anionic amino acids could contribute to the selectivity pattern of the synthesized compounds.