Pharmacology and Mechanism of Action of Peptides in the Brain

A special issue of Pharmaceuticals (ISSN 1424-8247). This special issue belongs to the section "Pharmacology".

Deadline for manuscript submissions: 25 August 2025 | Viewed by 361

Special Issue Editor

Special Issue Information

Dear Colleagues,

This Special Issue aims to cover recent progress in the pharmacology and brain activity of endogenous and newly synthetized peptide derivatives and peptidomimetics. Brain peptides play crucial roles as neurotransmitters, neuromodulators, and neuroprotective agents. They are involved in a wide range of physiological functions, including pain modulation, stress response, seizure susceptibility, appetite regulation, and the sleep–wake cycle. Their mechanisms of action typically involve receptor binding, whereby peptides exert their effects by binding to specific receptors on the surface of neurons or other cell types. Most neuropeptides act on protein-coupled receptors, which can initiate intracellular signaling cascades upon activation, such as cyclic AMP signaling or the inositol trisphosphate pathway. This pathway can lead to the release of calcium from the endoplasmic reticulum, affecting cellular functions. Neuropeptides can modulate neurotransmitter release and synaptic strength, enhance or inhibit the effects of classical neurotransmitters like glutamate or GABA, influencing overall neuronal excitability and circuit dynamics, and lead to long-term changes in gene expression and neuronal plasticity, impacting learning and memory processes. The dysregulation of peptide systems is implicated in various conditions, including epilepsy, depression, anxiety, schizophrenia, and neurodegenerative diseases. For example, targeting opioid receptors can provide analgesic effects or alter one’s mood. Peptides’ therapeutic applications are due to their specific actions: for instance, peptide antagonists and agonists are versatile molecules with complex roles in neural function. Understanding their pharmacology and mechanisms of action is essential for developing novel therapeutic strategies for neuropsychiatric and neurological disorders. Further research into peptide signaling pathways and receptor interactions continues to be a prominent area of study in neuroscience and pharmacology.

This Special Issue will publish original high-quality papers, short commentaries, and comprehensive reviews presenting results and insights related to the pharmacology and mechanisms of action of endogenous and newly synthetized peptide derivatives and peptidomimetics. These reports may come from disciplines ranging from chemistry to neuroscience, characterizing peptide molecules in animal models of neurodegenerative diseases.

Dr. Jana Tchekalarova
Guest Editor

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Keywords

  • peptide derivatives
  • neuropeptides
  • receptors
  • brain
  • pain
  • epilepsy
  • depression
  • anxiety

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Published Papers (1 paper)

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18 pages, 8225 KiB  
Article
Anticonvulsant Profiles of Three Hemorphin-4 Analogs with Rhodamine B in Mice
by Jana Tchekalarova, Miroslav Rangelov, Ivan Iliev, Nadezhda Todorova, Tsveta Stoyanova, Lian Nedelchev and Petar Todorov
Pharmaceuticals 2025, 18(5), 673; https://doi.org/10.3390/ph18050673 - 1 May 2025
Viewed by 104
Abstract
Background/Objectives: Hemorphins, considered to be bioactive atypical oligopeptides, are products of hemoglobin metabolism. Recently, our team reported the synthesis and characterization of three N-modified analogs of hemorphin-4 (H4) with rhodamine B (Rh). In the present study, the Rh-1, Rh-2, and Rh-3 compounds [...] Read more.
Background/Objectives: Hemorphins, considered to be bioactive atypical oligopeptides, are products of hemoglobin metabolism. Recently, our team reported the synthesis and characterization of three N-modified analogs of hemorphin-4 (H4) with rhodamine B (Rh). In the present study, the Rh-1, Rh-2, and Rh-3 compounds were intracerebroventricularly infused at doses of 1, 2.5, 5, and 10 µg/5 µL, respectively, and evaluated for their antiseizure activity in 6-Hz and maximal electroshock (MES) tests and in a pentylenetetrazol (PTZ)-induced kindling model in mice. Phenytoin and diazepam were used as the reference drugs. The role of opioid receptors (ORs) underlying their mechanism of action was also evaluated in silico and pharmacologically. Results: The three Rh-H4 compounds showed a good safety profile at a concentration of 100 µg/mL in the mouse embryonic fibroblasts. They suppressed psychomotor seizures and seizure spreading as follows: Rh-1 at doses of 5 and 10 µg/5 µL, Rh-2 at the highest dose, and Rh-3 at doses of 1–10 µg/5 µL, respectively. Administered at doses of 5 µg/5 µL (Rh-1 and Rh-3) and 10 µg/5 µL (Rh-2), the compounds suppressed clonic seizures in the kindled mice comparable to the reference drug diazepam. A combination of selective delta (DOR), kappa (KOR), and mu (MOR) OR antagonists with the highest doses of the Rh-1, Rh-2, and Rh-3 compounds was used to elucidate the possible role of ORs in the underlying mechanism related to their protective activity against seizure spread. Only the selective DOR antagonist, natrindole, suppressed the effect of the Rh-1 peptide analog on seizures. The OR antagonist naloxone prevented the antiseizure activity of Rh-1 in the kindled mice. The results of docking analysis also showed the model-specific interaction of the three Rh-H4 compounds with the OR. Conclusions: Our results suggest that the antiseizure activity of Rh-1 is mediated by the OR, and in particular by the DOR, while the mechanism underlying the antiseizure effect of Rh-3 is more complex and may involve other receptors. Full article
(This article belongs to the Special Issue Pharmacology and Mechanism of Action of Peptides in the Brain)
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