Proline Homologation in Melanostatin Neuropeptide: Discovery of Potent Modulators of the Dopamine D Receptors.

Melanostatin (MIF-1) is a naturally occurring neuropeptide acting as a positive allosteric modulator (PAM) of dopamine D receptors (DR), underscoring its potential for therapeutic use in central nervous system disorders associated with dopaminergic dysregulation, including depression, drug addiction, restless legs syndrome, tardive dyskinesia, and Parkinson's disease. In this work, a new series of MIF-1 analogs using l-pipecolic acid as an l-proline surrogate was synthesized and pharmacologically evaluated by functional assays at the DR. In this series, methyl l-pipecolyl-l-leucylglycinate () was found to exhibit superior performance compared to MIF-1 by promoting a 4.

Discovery of hybrid Glypromate conjugates with neuroprotective activity against paraquat-induced toxicity.

Neurodegenerative disorders comprise a series of heterogeneous conditions that affect millions of people worldwide, representing a significant health burden in both developed and developing countries. Without disease-modifying treatments currently available, the development of effective neurotherapeutics is a health priority. In this work, a new series of peptide-conjugates of the Glypromate neuropeptide is reported to determine the interplay of annular constriction and neuroprotective activity.

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

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 receptors (DR) showed that bioconjugates (EC = 26.39 ± 3.

Concise Overview of Glypromate Neuropeptide Research: From Chemistry to Pharmacological Applications in Neurosciences.

Neurodegenerative diseases of the central nervous system (CNS) pose a serious health concern worldwide, with a particular incidence in developed countries as a result of life expectancy increase and the absence of restorative treatments. Presently, treatments for these neurological conditions are focused on managing the symptoms and/or slowing down their progression. As so, the research on novel neuroprotective drugs is of high interest.

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

Neurodegenerative disorders of the central nervous system are a class of heterogeneous pathologies affecting millions of people worldwide and represent a global health burden in developed and developing countries. Without restorative treatments currently available, research on neuroprotective drugs is considered a health priority. In this study, new analogues of the glycyl-l-prolyl-l-glutamic acid (Glypromate) neuropeptide were designed, synthesized, and biologically evaluated using (1,3,4)-2-azanorbornane-3-carboxylic acid as a hybrid construct of l-proline and l-pipecolic acid.

Breaking Barriers: Bioinspired Strategies for Targeted Neuronal Delivery to the Central Nervous System.

Central nervous system (CNS) disorders encompass a vast spectrum of pathological conditions and represent a growing concern worldwide. Despite the high social and clinical interest in trying to solve these pathologies, there are many challenges to bridge in order to achieve an effective therapy. One of the main obstacles to advancements in this field that has hampered many of the therapeutic strategies proposed to date is the presence of the CNS barriers that restrict the access to the brain.

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

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 -propylapomorphine ([H]-NPA) at dopamine D receptors (DR). Methyl picolinoyl-l-valyl-l-alaninate (compound ) produced a statistically significant increase in the maximal [H]-NPA response at 0.

Highly efficient one-pot assembly of peptides by double chemoselective coupling.

This study describes a methodological advancement in solution-phase peptide synthesis via the development of a convenient and operational protocol to synthesize oligopeptides in a one-pot three-step cascade method, in which two peptide bonds are introduced chemoselectively. Tri- to hexapeptides were obtained in high global yields (80-95%) with virtually no epimerization as determined via HPLC. The methodology described herein represents a faster, easier and milder approach to the synthesis of peptides, and it operates at equimolar amounts.