Biological activity of endomorphin and [Dmt1]endomorphin analogs with six-membered proline surrogates in position 2.
Endogenous mu-opioid receptor (MOR) selective peptides, endomorphin-1 (EM-1) and endomorphin-2 (EM-2), unlike so called 'typical opioids', are characterized by the presence of Pro(2) residue, which is a spacer connecting aromatic pharmacophoric residues. In order to investigate structural requirements for position 2, we synthesized endomorphin analogs incorporating, instead of Pro, unnatural amino acids with six-membered heterocyclic rings, such as piperidine 2-, 3- or 4-carboxylic acids (Pip, Nip and Inp, respectively). (R)-Nip residue turned out to be favourable for improving MOR affinity. Introduction of 2',6'-dimethyltyrosine (Dmt) instead of Tyr(1) led to obtaining [Dmt(1), (R)-Nip(2)]EM-2 which showed exceptional MOR affinity and high stability against enzymatic degradation in rat brain homogenate. In in vivo hot-plate test in mice, this analog given intracerebroventicularly (i.c.v.), produced profound supraspinal analgesia, being much more potent than EM-2. The antinociceptive effect of this analog lasted about 170 min and was almost completely reversed by beta-funaltrexamine (beta-FNA), a selective MOR antagonist.
Laboratory of Biomolecular Chemistry, Institute of Biomedicinal Chemistry, Medical University of Lodz, Mazowiecka 6/8, 92-215 Lodz, Poland.
Renata
R
Perlikowska
Katarzyna
K
Gach
Jakub
J
Fichna
Geza
G
Toth
Bogdan
B
Walkowiak
Jean-Claude
JC
do-Rego
Anna
A
Janecka
D000595:Amino Acid Sequence; D000700:Analgesics / Q000737:chemistry / Q000494:pharmacology; D000701:Analgesics, Opioid / Q000737:chemistry* / Q000494:pharmacology; D000818:Animals; D001921:Brain / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D004305:Dose-Response Relationship, Drug; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D015394:Molecular Structure; D009842:Oligopeptides / Q000737:chemistry* / Q000494:pharmacology; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry; D011392:Proline / Q000737:chemistry* / Q000378:metabolism; D051381:Rats
D000700:Analgesics; D000701:Analgesics, Opioid; D009842:Oligopeptides; D010455:Peptides; C105293:endomorphin 1; D011392:Proline