Peripherally active tetrapeptides as selective κ opioid receptor (KOR) agonists have been prepared in good overall yields and high purity following solid-phase peptide synthesis via Fmoc protection strategy. Structural modifications at the first and second position of the FF(d-Nle)R-NH () were contemplated with aromatic side chains containing d-amino acids, such as (d)-F-Phe, (d)-F-Phe, (d)-F-Phe, which led to highly selective and efficacious KOR agonists endowed with strong antinociceptive activity following intravenous (i.v.) and subcutaneous (s.c.) administration in the tail flick and formalin tests. These results suggest potential clinical applications in the treatment of neuropathic and inflammatory pain.
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