An Interactive SAR Approach to Discover Novel Hybrid Thieno Probes as Ligands for D2‐Like Receptors with Affinities in the Subnanomolar Range

Abstract

A series of [(phenylpiperazinyl)alkyl]-isoindole-1,3-dione derivatives was synthesized to serve as probes for dopaminergic receptors. Among this series, compound 6a showed the highest affinity towards D4 and D3 receptors with Ki values in the low nanomolar range, and D2/D4- and D2/D3-selectivity indices of 72 and 20, respectively. Optimization rounds were adopted and led to the D4-selective ligand thiophene-2-carboxamide 9a with a Ki (D4) value of 0.62 nM, and to its butyl analog, 10a, with Ki (D4) and Ki (D3) values of 0.03 and 0.26 nM, respectively. Docking experiments revealed the importance of the unique D4 residue Arg186 in manipulating the ligands' D4-subtype-receptor selectivity.

Benzyl Phenylsemicarbazides: A Chemistry-Driven Approach Leading to G Protein-Biased Dopamine D4 Receptor Agonists with High Subtype Selectivity

“…R f : 0.4 (methylene chloride/methanol = 50:1) [UV]; 1 H NMR (400 MHz, CDCl 3 ): δ (ppm) 1.84 (dp, J = 7.1 Hz, J = 13.8 Hz, 2H), 2.32–2.51 (m, 6H), 2.90 (dd, J = 7.5 Hz, J = 12.6 Hz, 4H), 3.70 (t, J = 6.9 Hz, 2H), 6.62–6.70 (m, 2H), 7.03–7.12 (m, 2H), 7.55–7.62 (m, 2H), 7.69–7.77 (m, 2H); 13 C NMR (101 MHz, DEPTQ, CDCl 3 ): δ (ppm) 25.3 (CH 2 ), 36.7 (CH 2 ), 49.1 (2 × CH 2 ), 53.1 (2 × CH 2 ), 56.1 (CH 2 ), 117.3 (2 × CH), 123.3 (2 × CH), 124.6 (C q ), 129.0 (2 × CH), 132.4 (2 × C q ), 134.0 (2 × CH), 149.9 (C q ), 168.6 (2 × C q ). The analytical data obtained is in agreement with those reported in literature …”

Structure–Activity Relationships of Privileged Structures Lead to the Discovery of Novel Biased Ligands at the Dopamine D2 Receptor

“…Ethyl 3-Amino-6-methoxy-4-methylthieno[2,3-b]pyridine-2carboxylate (28). Compound 27 (1.52 g, 6.02 mmol) was added to N,N-dimethylformamide (20 mL) followed by potassium carbonate (1.25 g, 9.04 mmol) and methyl iodide (0.41 mL, 6.63 mmol).…”

“…Additionally, the use of a thiophene has previously been shown to be advantageous in increasing the affinity for D 2 -like receptor subtypes, relating to its electron-rich system and its ability to form hydrophobic interactions within a binding pocket, essentially acting as an isostere of benzene. 28 As such, we envisioned that our thienopyridine scaffolds may also exhibit these properties. The ligands generated were evaluated using in vitro assays to measure their ability to displace through activation of the D 2 R. For selected compounds, we extended our characterization to a second functional assay, inhibition of forskolin-induced cAMP production, to allow identification and quantification of biased agonism.…”

“…In order to convert the pyridinone into the corresponding pyridine alkyl ether, 27 was reacted with iodomethane under basic conditions. One equivalent of a stronger base, such as 1 M aqueous potassium hydroxide, was necessary to ensure complete conversion to the thienopyridine scaffold (28). It was imperative to protect the free amine of the bicycle prior to chlorination at the 5′ position to avoid N-halogenation.…”

α-Adrenoceptor antagonistic and hypotensive properties of novel arylpiperazine derivatives of pyrrolidin-2-one

“…[17][18][19] Firstly, substituted arylpiperazines were alkylated with 2-(2-bromoethyl)isoindoline-1,3-dione (1) or 2-(4-bromobutyl)isoindoline-1,3-dione (2) 20 to give the phthalimide derivatives 3a-e and 4c-i. The amine functionality of the compounds was liberated using hydrazine hydrate.…”