Selective Antagonism at Dopamine D3 Receptors as a Target for Drug Addiction Pharmacotherapy: A Review of Preclinical Evidence

Abstract

The focal distribution of the dopamine (DA) D(3) receptor in brain regions implicated in emotional and cognitive functions has made this target a main focus of drug discovery efforts. This paper will review the most recent lines of research in support of the use of selective DA D(3) receptor antagonists for the pharmacotherapeutic management of drug addiction: (1) expression of the DA D(3) receptor in the rodent and human brain; (2) changes in expression of the DA D(3) receptor following exposure to drugs of abuse, and (3) efficacy of selective DA D(3) receptor antagonists in preclinical paradigms assessing the behavioral effects of drugs such as cocaine, nicotine, alcohol, methamphetamine, and heroin. This manuscript, however, will not review the effects of nonselective DA D(2)/D(3) receptor antagonists or partial D(3) receptor agonists. Growing evidence suggests that selective DA D(3) receptor antagonists do not affect the primary reinforcing effects of drugs of abuse, but rather seem to regulate the motivation to self-administer drugs under schedules of reinforcement that require an increase in work demand. In addition, selective antagonism at DA D(3) receptors appears to disrupt significantly the responsiveness to drug-associated stimuli that play a key role in reinstatement of drug-seeking behavior. These preclinical findings will be discussed in the context of translational research relevant to the design of early clinical trials and hypothesis testing in humans.

Triazolyl Azabicyclo[3.1.0]hexanes: a Class of Potent and Selective Dopamine D3 Receptor Antagonists

“…General synthetic approach to derivatives 6-8 and 10-46 (R = H, F, Me). Reagents and conditions: a) NH 2 NH 2 ·H 2 O, CH 3 OH, D, 608C (reflux), 3 h; b) 49, K 2 CO 3 , 608C (reflux), overnight; c) supported OsO 4 , NaIO 4 , THF, room temperature, overnight; d) 52, NaBH(OAc) 3 , AcOH, THF, room temperature, 2 h. single-point energy calculation was carried out using B3LYP density functional theory with a 6-31G* basis set. The electrostatic potential (measured in kcal mol À1 ) was finally mapped onto the electronic density surface of the atoms (at an isosurface level of 0.002 electrons AU…”

“…The first round of compounds for this exploration (10-22) was chosen so that the Clog D values of the heteroaromatic substituents could range from 1 to 4 to determine whether, in this specific series as well, a correlation with DA D 3 affinity is present, as in the thiotriazole series. It is apparent that the derivatives with the best overall activity do fall within the previously described "ideal" Clog D range (3)(4), with some of these endowed with high nanomolar affinity (compounds 12, 15, 20, and 21). In this series, a further important aspect of this exploration is the knowledge gained about the role played by the substituents in hERG activity.…”

“…Volatiles were evaporated in vacuo to give 178 mg 4-(4-methyl-5-phenyl-4H-1,2,4-triazol-3-yl)butanal as an oil, which was used in the subsequent step without further purification. A mixture this derivative (0.38 mmol), (1S,5R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane (0.28 mmol), NaBH(OAc) 3 (0.28 mmol), and AcOH in THF (anhydrous, 2 mL) was stirred at room temperature for 2 h. The organic phase was washed with 1 n NaOH, dried over Na 2 SO 4 , and filtered. The filtrate was concentrated in vacuo, and the crude was purified by column chromatography to give 38 mg of the free base of compound 6.…”

“…[1] The expression pattern of D 3 mRNA in rat and human brain are similar, with high expression levels primarily in areas of the limbic system. Different anatomical, pharmacological, and genetic findings suggest that the DA D 3 receptor might be involved in Parkinson's disease, schizophrenia, and drug addiction. [2] The specific location of the DA D 3 receptor in both the rodent and human brain, the alterations in the expression of the D 3 receptor after exposure to drugs of abuse, and growing preclinical evidence suggest that selective DA D 3 receptor antagonists are suitable candidates for the pharmacotherapeutic management of drug addiction.…”

“…[2] The specific location of the DA D 3 receptor in both the rodent and human brain, the alterations in the expression of the D 3 receptor after exposure to drugs of abuse, and growing preclinical evidence suggest that selective DA D 3 receptor antagonists are suitable candidates for the pharmacotherapeutic management of drug addiction. [3] Among the many research groups in this field, [2][3][4][5][6][7][8] GlaxoSmithKline (GSK) has actively contributed to the discovery of selective DA D 3 receptor antagonists. [9][10][11][12][13][14][15][16] Some recently disclosed compounds are shown in Figure 1.…”