Synthesis and biological activity of endomorphin-2 analogs incorporating piperidine-2-, 3- or 4-carboxylic acids instead of proline in position 2.
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.
Laboratory of Biomolecular Chemistry, Institute of Biomedicinal Chemistry, Medical University, Lodz, Poland.
Renata
R
Staniszewska
Jakub
J
Fichna
Katarzyna
K
Gach
Geza
G
Toth
Jeroen
J
Poels
Jozef
J
Vanden Broeck
Anna
A
Janecka
D019943:Amino Acid Substitution; D000818:Animals; D001923:Brain Chemistry; D002264:Carboxylic Acids / Q000737:chemistry*; D020128:Inhibitory Concentration 50; D009842:Oligopeptides / Q000737:chemistry*; D010880:Piperidines / Q000737:chemistry*; D011392:Proline; D051381:Rats; D017450:Receptors, Opioid, mu / Q000037:antagonists & inhibitors*
D002264:Carboxylic Acids; D009842:Oligopeptides; D010880:Piperidines; D017450:Receptors, Opioid, mu; C105294:endomorphin 2; D011392:Proline