Identification
and Characterization of ML321: A Novel
and Highly Selective D2 Dopamine Receptor Antagonist with
Efficacy in Animal Models That Predict Atypical Antipsychotic Activity
posted on 2022-12-30, 19:12authored byR. Benjamin Free, Ashley N. Nilson, Noelia M. Boldizsar, Trevor B. Doyle, Ramona M. Rodriguiz, Vladimir M. Pogorelov, Mayako Machino, Kuo Hao Lee, Jeremiah W. Bertz, Jinbin Xu, Herman D. Lim, Andrés E. Dulcey, Robert H. Mach, James H. Woods, J Robert Lane, Lei Shi, Juan J. Marugan, William C. Wetsel, David R. Sibley
We have developed and characterized a novel D2R antagonist
with
exceptional GPCR selectivity – ML321. In functional profiling
screens of 168 different GPCRs, ML321 showed little activity beyond
potent inhibition of the D2R and to a lesser extent the D3R, demonstrating
excellent receptor selectivity. The D2R selectivity of ML321 may be
related to the fact that, unlike other monoaminergic ligands, ML321
lacks a positively charged amine group and adopts a unique binding
pose within the orthosteric binding site of the D2R. PET imaging studies
in non-human primates demonstrated that ML321 penetrates the CNS and
occupies the D2R in a dose-dependent manner. Behavioral paradigms
in rats demonstrate that ML321 can selectively antagonize a D2R-mediated
response (hypothermia) while not affecting a D3R-mediated response
(yawning) using the same dose of drug, thus indicating exceptional in vivo selectivity. We also investigated the effects of
ML321 in animal models that are predictive of antipsychotic efficacy
in humans. We found that ML321 attenuates both amphetamine- and phencyclidine-induced
locomotor activity and restored pre-pulse inhibition (PPI) of acoustic
startle in a dose-dependent manner. Surprisingly, using doses that
were maximally effective in both the locomotor and PPI studies, ML321
was relatively ineffective in promoting catalepsy. Kinetic studies
revealed that ML321 exhibits slow-on and fast-off receptor binding
rates, similar to those observed with atypical antipsychotics with
reduced extrapyramidal side effects. Taken together, these observations
suggest that ML321, or a derivative thereof, may exhibit ″atypical″
antipsychotic activity in humans with significantly fewer side effects
than observed with the currently FDA-approved D2R antagonists.