In vivo Behavioral Characterization of ML417, a Novel D3 Dopamine Receptor‐selective Agonist

Abstract

Dopamine receptor (DAR) agonists are important in the therapeutics of Parkinson's disease, Restless Legs Syndrome, and other neurologic disorders. Dopamine receptors are divided into D1‐like (D1R and D5R) and D2‐like (D2R, D3R, and D4R) subcategories. Subtype‐selective DAR agonists can potentially impart pharmacologic benefits while decreasing adverse effects seen with nonselective treatments. However, significant homology exists among the DAR subtypes, especially D2Rs and D3Rs rendering the development of subtype‐selective agonists challenging. Using a high‐throughput screening drug discovery program, we have identified and optimized a highly selective and potent D3R agonist (ML417) as determined using in vitro assays. We also found that ML417 exhibited good pharmacokinetics in mice with a t1/2 of 3–4 hrs in both plasma and brain. In this study, we tested ML417 using several behavioral paradigms in rats. Pramipexole and quinpirole, two relatively non‐selective D2R/D3R agonists in clinical use, were utilized as comparators. All behavioral experiments were approved by the NIH Institutional Animal Care and Use Committee (IACUC). Assessment of locomotor activity was carried out in an open field. Rat behavior was recorded with horizontal and vertical video cameras over a period of 90 mins following i.p. administration. Locomotor activity was tracked with ANY‐maze® software. Yawning ‐ a behavior mediated by D3R activation ‐ was scored by a blinded rater. Rats received multiple doses of ML417, quinpirole or pramipexole in a pseudorandom fashion for all studies. Stereotypies, catalepsy, and other adverse effects were measured, but were not significant at any dose of the drugs tested. During the initial 30 mins after drug administration, quinpirole and pramipexole induced dose‐dependent hypolocomotion (distance traveled or rotational behaviors) in the open field, as has been observed previously. ML417 similarly induced hypolocomotion during the initial 30 min in the open field, but only at the highest dose tested (20 mg/kg). In contrast, between 60–90 mins in the open field, the rats treated with either quinpirole and pramipexole became hyperactive, vs. controls, whereas the animals treated with ML417 were not different from vehicle‐treated animals. These differences in the locomotor effects of ML417 vs. quinpirole or pramipexole during the 60–90 time period post‐drug administration may be due to the D3R selectivity of ML417. We also observed with the 20 mg/kg dose, that ML417 induced significant yawning behavior, which is a known D3R‐mediated behavioral response. These results suggest that ML417 is capable of stimulating the D3R in vivo and does not result in observable side effects. These behavioral effects can be differentiated from non‐ or less‐selective D2‐like DAR agonists. Further studies utilizing ML417 in animal models of disease states, such as Parkinson's disease, are warranted and will enhance our understanding of the role of D3R stimulation in the treatment of neurological disorders.Support or Funding InformationNIH IRPThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.