Highly Selective Dopamine D₃ Receptor (D₃R) Antagonists and Partial Agonists Based on Eticlopride and the D₃R Crystal Structure: New Leads for Opioid Dependence Treatment

Abstract

The recent and precipitous increase in opioid analgesic abuse and overdose has inspired investigation of the dopamine D3 receptor (D3R) as a target for therapeutic intervention. Metabolic instability or predicted toxicity has precluded successful translation of previously reported D3R-selective antagonists to clinical use for cocaine abuse. Herein, we report a series of novel and D3R crystal structure-guided 4-phenylpiperazines with exceptionally high D3R affinities and/or selectivities with varying efficacies. Lead compound 19 was selected based on its in vitro profile: D3R Ki = 6.84 nM, 1700 fold D3R versus D2R binding selectivity, and its metabolic stability in mouse microsomes. Compound 19 inhibited oxycodone-induced hyperlocomotion in mice and reduced oxycodone-induced locomotor sensitization. In addition, pretreatment with 19 also dose-dependently inhibited the acquisition of oxycodone-induced conditioned place preference (CPP) in rats. These findings support the D3R as a target for opioid dependence treatment and compound 19 as a new lead molecule for development.

Effects of the selective dopamine D3receptor antagonist PG01037 on morphine-induced hyperactivity and antinociception in mice

“…Our results suggest that the robust attenuation of morphine-induced locomotion previously observed with nonselective D2-like receptor antagonism is primarily attributable to blockade of the D2R subtype. Moreover, our finding that pretreatment with the selective D3R antagonist PG01037 produces a significant, albeit weaker, attenuation of morphine-induced locomotion is in accord with a number of recent studies that also demonstrate modest reductions of the locomotor-activating effects of opioids following pretreatment with other highly-selective D3R antagonists (Kumar et al 2016;Lv et al 2019;You et al 2017). Based on these prior findings and our present results with PG01037 and L-741,626, we conclude that D3R antagonism and D2R antagonism exert qualitatively similar reductions of morphine-induced hyperlocomotion, however a pharmacological shift away from D3R selectivity towards either nonselective antagonism or selective D2R antagonism renders this modulation far more robust.…”

“…Consequently, D3R antagonism may "mask" the overt appearance of sensitization during the induction phase due to its capacity to attenuate morphine-induced hyperactivity, but the development of the underlying sensitization can be "unmasked" and observed when morphine is tested in the absence of D3R antagonism. It is noteworthy that this hypothesis is in conflict with a recent report that pretreatment with the highly-selective D3R antagonist VK4-116 attenuated the induction of oxycodone-induced locomotor sensitization (Kumar et al 2016) as assessed by a challenge test with oxycodone alone. However, some key procedural differences may underlie these discrepant findings including the use of different opioids (morphine vs. oxycodone), use of different D3R antagonists (PG01037 vs. VK4-116), and imposition of 7 days vs. 2 days between the final induction session and the expression test.…”

Targeting hypersensitive corticostriatal terminals in restless legs syndrome

“…29 Three D 2 -like receptor antagonists were then chosen to disclose the possible contribution of D4R and D2SR in the effect of pramipexole: L745-870, with selective high affinity for D4R [30][31][32] ; raclopride, with high affinity for D2R and D3R but low affinity for D4R 31,32 ; and VK4-116, a recently introduced compound with selective high affinity for D3R. 25 The in vitro recovery of these compounds through the optogenetic-microdialysis probe at the same flow rate used in the in vivo experiments (1 ml/min), as analyzed by HPLC (see Materials and Methods), was 12.0 6 0.7%, 8.2 6 0.2%, and 20.6 6 0.6% for L745-870, raclopride, and VK4-116, respectively. These figures provide an approximation to the effective extracellular concentration of drugs administered through the microdialysis probe (reverse dialysis).…”

“…33 The concentration of the D 2 -like receptor antagonists in the perfusion media (10 lM) should therefore yield extracellular concentrations around the probe of around 1 lM or lower, which would be insufficient for L745-870 to bind significantly to D2R or D3R, for raclopride to bind to D4R, and for VK4-116 to bind to D2R or D4R. 25,[30][31][32] Coperfusion with 10 lM of L745-870 or raclopride, but not VK4-116, significantly counteracted the effect of pramipexole (1 lM), and the optogenetic stimulation could still increase glutamate release both in controls (at 100Hz) and in animals with BID (at 60Hz; Fig 3A, B). The results therefore imply a participation of both D4R and D2SR, but not D3R, in the effect of pramipexole.…”

Synthetic route towards potential bivalent ligands possessing opioid and D2/D3 pharmacophores

“…It was found that the drugs affecting the dopaminergic system can also influence the effect of opioid agonists on cognitive functions in animal models. [7][8][9][10][11][12][13][14] These results are expected to be useful for further understanding of the tolerance and dependence phenomena in opioids addiction.…”