Development of novel multipotent compounds modulating endocannabinoid and dopaminergic systems

Area of Science:

• Medicinal Chemistry
• Neuroscience
• Pharmacology

Background:

• Polypharmacology offers a promising strategy for developing treatments for complex diseases, addictions, and smoking cessation.
• The endocannabinoid and dopaminergic systems are intricately interconnected and play crucial roles in various physiological and pathological processes.

Purpose of the Study:

• To design and synthesize novel molecules that modulate both the endocannabinoid and dopaminergic systems by merging pharmacophoric elements of existing leads.
• To evaluate the pharmacological properties, drug-likeness, and safety profiles of the newly synthesized compounds.

Main Methods:

• Synthesis of novel compounds (5a-j) inspired by fatty acid amide hydrolase (FAAH) inhibitors and dopamine D2/D3 receptor ligands.
• In silico drug-likeness assessment.
• Experimental evaluation of hERG affinity, selectivity, cytotoxicity (fibroblast, astrocytes, neuroblastoma cell line IMR 32), and mutagenicity (Ames test).
• Metabolic studies for selected compounds (3a, 5c).

Main Results:

• The majority of synthesized compounds (5a-j) exhibited nanomolar potency against the targeted receptors.
• Compounds demonstrated favorable drug-likeness, low cytotoxicity, and no mutagenicity.
• Compounds 3a and 5c showed a potential anti-inflammatory profile in the IMR 32 neuroblastoma cell line without significant toxicity.

Conclusions:

• The developed compounds represent potential pharmacological tools for studying or treating complex diseases involving the endocannabinoid and dopaminergic systems.
• The novel molecules possess promising pharmacological and safety profiles, warranting further investigation for therapeutic applications.