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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