Identification of a new selective dopamine D4 receptor ligand

Abstract

The dopamine D4 receptor has been shown to play key roles in certain CNS pathologies including addiction to cigarette smoking. Thus, selective D4 ligands may be useful in treating some of these conditions. Previous studies in our laboratory have indicated that the piperazine analog of haloperidol exhibits selective and increased affinity to the DAD4 receptor subtype, in comparison to its piperidine analog. This led to further exploration of the piperazine moiety to identify new agents that are selective at the D4 receptor. Compound 27 (KiD4 = 0.84 nM) was the most potent of the compounds tested. However, it only had moderate selectivity for the D4 receptor. Compound 28 (KiD4 = 3.9 nM) while not as potent, was more discriminatory for the D4 receptor subtype. In fact, compound 28 has little or no binding affinity to any of the other four DA receptor subtypes. In addition, of the 23 CNS receptors evaluated, only two, 5HT1AR and 5HT2BR, have binding affinity constants better than 100 nM (Ki < 100 nM). Compound 28 is a potentially useful D4-selective ligand for probing disease treatments involving the D4 receptor, such as assisting smoking cessation, reversing cognitive deficits in schizophrenia and treating erectile dysfunction. Thus, further optimization, functional characterization and evaluation in animal models may be warranted.

Synthesis and evaluation of the structural elements in alkylated tetrahydroisoquinolines for binding to CNS receptors

“…Using the previously reported alkylating agent 2-(2-chloroethyl)-5-fluoro-2,3-dihydro-1H-inden-1-one ( 25 ), 20, 21 THIQ was alkylated under alkylation method B to afford compound 3h in 23% yield. Mp 240-241 °C; 1 H NMR (DMSO- d 6 ): 7.73 (dd, J = 5.8, 8.4 Hz, 1H), 7.45 (d, J = 9.0 Hz, 1H), 7.24 (m, 5H), 4.52 (m, 2H), 4.28 (m, 2H), 3.68 (m, 1H), 3.34 (m, 6H), 2.99 (m,1H), 2.89 (m, 2H), 2.31 (m, 1H), 1.99 (m, 1H).…”

“…Under the general alkylation method B , the previously described alkylating agent 2-(2-chloroethyl)-2,3-dihydro-1H-inden-1-one ( 26 ) 20 was coupled to THIQ to afford compound 3i as the HCl salt in 65% yield. Mp: 201-203 °C.…”

“…18 Compound 1b was prepared by coupling 2-(3-chloropropyl)benzo[d]thiazole ( A ) previously reported by us 18,20-21 ( Figure 2 ) to 1,2,3,4-tetrahydro-isoquinoline (THIQ) under the general alkylation condition B (4.1.2) that used K 2 CO 3 as the base, KI as a catalyst and either acetonitrile (CH 3 CN) or dimethoxyethane (DME) as the refluxing solvent. Alkylating agent C was synthesized according to a modified literature method 22 outlined in Scheme 1 and was reacted with THIQ to afford compound 1d (Scheme 2 ).…”

“…Compounds 3h - j were prepared by N-alkylating THIQ using the indanone alkylating agents 25-27 previously reported by our lab ( Scheme 8 ). 20, 21 …”

Homology modeling, molecular dynamic simulation, and docking based binding site analysis of human dopamine (D4) receptor

“…ML398 has been presented as a selective D4 antagonist in recent studies [10]. Moreover, some selective ligands exhibited remarkable binding affinity to 5HT 1A R ,5HT 2A R, and 5HT 2B R [11,12]. A SAR study of selective D4 ligands reported an important arene-cation interaction between the ligands arene moiety and the residue Arg-186.…”