Synthesis and biological evaluation of strained unusual amino acid containing tetrapeptides as potential antidepressant agents

• Design and synthesis of GLYX-13 analogs using novel strained unusual β-amino acids.
• Compounds were studied for neurite growth, antidepressant properties.
• Forced swim test was performed for behavioural assay and compared with GLYX-13.
• Compounds 11a, 11b were studied for gene expression and neuroprotective property.
• Molecular docking study of synthesized compound in active site of NMDA receptors.

Strained unusual amino acid derived tetrapeptides were synthesized as mimics of GLYX-13, a clinical candidate for neuroprotective and anti-depressant properties, were studied. The synthesized compounds were screened for neurite growth and anti-depressant properties in vitro and in vivo respectively comparing with the parent GLYX-13 compound. Neurite growth property was assessed by neurite length and anti-depressant property by percentage of immobility in forced swim test, a behavioural assay. Mechanistic insights about protein–ligand interactions were obtained using molecular docking study. Based on the in vitro and in vivo screening data and molecular docking study, a new analogue of GLYX-13, Compound 11a has been found to be as good as the parent compound in all respects.

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