Synthesis and Biological Activity of Endomorphin‐2 Analogs Incorporating Piperidine‐2‐, 3‐ or 4‐Carboxylic Acids Instead of Proline in Position 2

Abstract

Novel endomorphin-2 (EM-2) analogs have been synthesized, incorporating unnatural amino acids with six-membered heterocyclic rings, such as piperidine-2-, 3- and 4-carboxylic acids (Pip, Nip and Inp, respectively) instead of Pro in position 2. [(R)-Nip(2)]EM-2 displayed an extremely high affinity for the mu-opioid receptor with IC(50) = 0.04 +/- 0.01 nM in comparison with IC(50) = 0.69 +/- 0.03 nM for EM-2. This analog was also very potent in the aequorin luminescence-based functional calcium assay and showed significantly enhanced stability in rat brain homogenate.