Discovery of New Potent Positive Allosteric Modulators of Dopamine D₂ Receptors: Insights into the Bioisosteric Replacement of Proline to 3-Furoic Acid in the Melanostatin Neuropeptide

Abstract

The control of Parkinson's disease (PD) is challenged by the motor and non-motor fluctuations as well as dyskinesias associated with levodopa long-term therapy. As such, pharmacological alternatives to reduce the reliance on this drug are needed. Melanostatin (MIF-1), a positive allosteric modulator (PAM) of D 2 receptors (D 2 R), is being explored as a novel pharmacological approach focused on D 2 R potentiation. In this work, 3-furoic acid (3-Fu) was successfully employed as an L-proline (Pro) surrogate, affording two potent MIF-1 analogues, methyl 3-furoyl-L-leucylglycinate (4a) and 3-furoyl-L-leucylglycinamide (6a). In this series, the C-terminal carboxamide moiety was found crucial to enhancing the potency and toxicological profile, yet it is not considered a requisite for the PAM activity. Conformational analysis excludes 4a from adopting the claimed type II β-turn. The discovery and validation of 6a as a lead compound open a new avenue for the development of a novel class of anti-Parkinson therapeutics targeting the D 2 R.

Stapling Amantadine to Melanostatin Neuropeptide: Discovery of Potent Positive Allosteric Modulators of the D2 Receptors

“…In this assay, MIF-1 exhibits the typical biphasic or bell-shaped concentration–response curve (Figure ). , This particular feature is widely described in the literature, ,,,,− including in vivo animal experiments, − and human clinical studies using MIF-1. ,, Delightfully, conjugates 1 and 2 statistically increased the DA effect by 10.3 ± 5.2% and 15.3 ± 6.3% at 0.01 nM (* p < 0.05), respectively, while MIF-1 exhibited a maximum DA effect at higher concentrations (31.9 ± 17.6% at 10 nM, * p < 0.05).…”

“…After in silico evaluation of these compounds as potential aggregators and/or pan-assay interference compounds (PAINS), functional assays were conducted for conjugates 1 and 2 in Chinese hamster ovary (CHO) cells expressing the human D 2 R to characterize their PAM activity by determination of the half-maximal effective concentration (EC 50 ) and maximal effect ( E max ). The assay is performed in the presence of dopamine (DA) to measure the inhibition of forskolin-stimulated cyclic adenosine monophosphate (cAMP) accumulation in response to D 2 R activation by homogeneous time-resolved fluorescence (HTRF). , …”

Design, Synthesis, and Biological Evaluation of Hybrid Glypromate Analogues Using 2-Azanorbornane as a Prolyl and Pipecolyl Surrogate

“…Considering the importance of nonspecific cytotoxicity during early drug development, the target compounds 2­(a-d) were screened in vitro for cytotoxicity on human adipose mesenchymal stem cells (hAd-MSCs), as previously reported. , In this assay, cell viability is estimated based on the ability of viable cells to reduce the tetrazolium compound 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2 H -tetrazolium, inner salt (MTS), into the corresponding formazan derivative by functional mitochondrial enzymes . The cytotoxicity results obtained from the MTS assay on hAd-MSC cells are depicted in Figure .…”

Allosteric Modulators of Dopamine D2 Receptors for Fine-Tuning of Dopaminergic Neurotransmission in CNS Diseases: Overview, Pharmacology, Structural Aspects and Synthesis

“…L-Prolyl-L-leucylglycinamide (PLG, Figure 6) is a CNS neuropeptide which has the ability to modulate D 2 receptors [39]. It is currently termed melanostatin (MIF-1) [40]. It potentiates the binding of agonists to this receptor (E max of 93.6 ± 4.4% for dopamine) [41][42][43][44] with no effect on antagonist binding; see Table 5 [41].…”

“…Compound 9 (see Figure 8) obtained within this series produced a statistically significant increase in the maximal [ 3 H]-NPA response at 0.01 nM (11.9 ± 3.7%) which indicates it is a PAM at D 2 receptor. Recently this group elaborated new PAMs of D 2 receptor based on the bioisosteric replacement of proline to 3-furoic acid in PLG (MIF-1) [40]. They obtained two potent MIF-1 analogues, methyl 3-furoyl-L-leucylglycinate (10a) and 3-furoyl-L-leucylglycinamide (10b), (Figure 8).…”