Synthesis, Pharmacological, and Biological Evaluation of MIF-1 Picolinoyl Peptidomimetics as Positive Allosteric Modulators of D2R

• Type: Article in International Scientific Journal
• Date: 2019

Authors

Sampaio Dias, IE (Author) Other; Silva Reis, SC (Author) Other; Garcia Mera, X (Author) Other; Brea, J (Author) Other; Isabel Loza, MI (Author) Other; Alves, CS (Author) Other; Algarra, M (Author) Other; Rodriguez Borges, JE (Author) FCUP

Journal

Title: Acs Chemical Neuroscience

Vol. 10

Pages: 3690-3702

ISSN: 1948-7193

Publisher: American Chemical Society

Indexing

ISI Web of Knowledge - 6 Citations

Scopus - 8 Citations

Other information

Authenticus ID: P-00Q-Z65

DOI: 10.1021/acschemneuro.9b00259

Abstract (EN): This work describes the synthesis and pharmacological evaluation of picolinoyl-based peptidomimetics of melanocyte stimulating hormone release inhibiting factor 1 (MIF-1) as dopamine modulating agents. Eight novel peptidomimetics were tested for their ability to enhance the maximal effect of tritiated N-propylapomorphine ([H-3]-NPA) at dopamine D-2 receptors (D2R). Methyl picolinoyl-L-valyl-L-alaninate (compound 6b) produced a statistically significant increase in the maximal [H-3]-NPA response at 0.01 nM (11.9 +/- 3.7%), which is close to the effect of MIF-1 in this assay at same concentration (18.3 +/- 9.1%). Functional assays measuring cAMP mobilization in the presence of dopamine corroborate the activity of peptidomimetic 6b as a positive allosteric modulator (PAM) of D2R. In this assay, 6b produced a typical bell-shaped dose-response curve similar to that of the parent neuropeptide (18.3 +/- 7.1% for 6b vs 15.4 +/- 5.5% for MIF-1, both at 0.1 nM). Dose-response curves for dopamine in the presence of 6b show EC50 (0.33 +/- 0.21 mu M for 6b vs 0.17 +/- 0.07 pM for MIF-1) and E-max (86.0 +/- 5.4% for 6b vs 93.6 +/- 4.4% for MIF-1) comparable to those of MIF-1, both at 0.01 nM. Furthermore, peptidomimetic 6b was tested for agonist activity at the human D2R and the results show that it displays no intrinsic agonism effect, endorsing its activity as a PAM of D2R. Cytotoxic and neurotoxic assays were performed for peptidomimetic 6b using HEK 293T cells and cortex neurons from 19 day old Wistar-Kyoto rat embryos, respectively, suggesting this analogue displays no toxicity effect in these assays up to 100 mu M. Conformational energy minimization for 6b shows that this peptidomimetic cannot adopt the postulated type-II beta-turn bioactive conformation, endorsing the possibility of an extended bioactive conformation as claimed by other researchers as a second bioactive conformation of MIF-1. Overall, the pharmacological and toxicological profile of peptidomimetic 6b together with its favorable druglike properties and structural simplicity makes it a potential lead compound for further development and optimization.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 25