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

• Type: Article in International Scientific Journal
• Date: 2023

Authors

Silva-Reis, SC (Author) Other; Correia, XC (Author) Other; Costa-Almeida, HF (Author) Other; Pires-Lima, BL (Author) Other; Maronde, D (Author) Other; Costa, VM (Author) Other; García-Mera, X (Author) Other; Luis Cruz (Author) FCUP; Brea, J (Author) Other; Loza, MI (Author) Other; Rodriguez Borges, JE (Author) FCUP; Sampaio-Dias, IE (Author) Other

Journal

Title: Acs Medicinal Chemistry Letters

Vol. 14

Pages: 1656-1663

ISSN: 1948-5875

Publisher: American Chemical Society

Indexing

ISI Web of Knowledge - 1 Citation

Scopus - 1 Citation

Other information

Authenticus ID: P-00Z-FJW

DOI: 10.1021/acsmedchemlett.3c00264

Abstract (EN): This work describes the synthesis and pharmacological and toxicological evaluation of melanostatin (MIF-1) bioconjugates with amantadine (Am) via a peptide linkage. The data from the functional assays at human dopamine D-2 receptors (hD(2)R) showed that bioconjugates 1 (EC50 = 26.39 +/- 3.37 nM) and 2 (EC50 = 17.82 +/- 4.24 nM) promote a 3.3- and 4.9-fold increase of dopamine potency, respectively, at 0.01 nM, with no effect on the efficacy (E-max = 100%). In this assay, MIF-1 was only active at the highest concentration tested (EC50 = 23.64 +/- 6.73 nM, at 1 nM). Cytotoxicity assays in differentiated SH-SY5Y cells showed that both MIF-1 (94.09 +/- 5.75%, p < 0.05) and carbamate derivative 2 (89.73 +/- 4.95%, p < 0.0001) exhibited mild but statistical significant toxicity (assessed through the MTT reduction assay) at 200 mu M, while conjugate 1 was found nontoxic at this concentration.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 8