PMID- 19435668
OWN - NLM
STAT- MEDLINE
DCOM- 20091008
LR  - 20131121
IS  - 1464-3391 (Electronic)
IS  - 0968-0896 (Linking)
VI  - 17
IP  - 11
DP  - 2009 Jun 1
TI  - Biological activity of endomorphin and [Dmt1]endomorphin analogs with 
      six-membered proline surrogates in position 2.
PG  - 3789-94
LID - 10.1016/j.bmc.2009.04.046 [doi]
AB  - 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.
FAU - Perlikowska, Renata
AU  - Perlikowska R
AD  - Laboratory of Biomolecular Chemistry, Institute of Biomedicinal Chemistry, 
      Medical University of Lodz, Mazowiecka 6/8, 92-215 Lodz, Poland.
FAU - Gach, Katarzyna
AU  - Gach K
FAU - Fichna, Jakub
AU  - Fichna J
FAU - Toth, Geza
AU  - Toth G
FAU - Walkowiak, Bogdan
AU  - Walkowiak B
FAU - do-Rego, Jean-Claude
AU  - do-Rego JC
FAU - Janecka, Anna
AU  - Janecka A
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20090503
PL  - England
TA  - Bioorg Med Chem
JT  - Bioorganic & medicinal chemistry
JID - 9413298
RN  - 0 (Analgesics)
RN  - 0 (Analgesics, Opioid)
RN  - 0 (Oligopeptides)
RN  - 0 (Peptides)
RN  - 0 (endomorphin 1)
RN  - 9DLQ4CIU6V (Proline)
SB  - IM
MH  - Amino Acid Sequence
MH  - Analgesics/chemistry/pharmacology
MH  - Analgesics, Opioid/*chemistry/pharmacology
MH  - Animals
MH  - Brain/drug effects
MH  - Chromatography, High Pressure Liquid
MH  - Dose-Response Relationship, Drug
MH  - Male
MH  - Mice
MH  - Molecular Sequence Data
MH  - Molecular Structure
MH  - Oligopeptides/*chemistry/pharmacology
MH  - Peptides/chemical synthesis/chemistry
MH  - Proline/*chemistry/metabolism
MH  - Rats
EDAT- 2009/05/14 09:00
MHDA- 2009/10/09 06:00
CRDT- 2009/05/14 09:00
PHST- 2009/01/23 00:00 [received]
PHST- 2009/04/20 00:00 [revised]
PHST- 2009/04/22 00:00 [accepted]
PHST- 2009/05/14 09:00 [entrez]
PHST- 2009/05/14 09:00 [pubmed]
PHST- 2009/10/09 06:00 [medline]
AID - S0968-0896(09)00406-4 [pii]
AID - 10.1016/j.bmc.2009.04.046 [doi]
PST - ppublish
SO  - Bioorg Med Chem. 2009 Jun 1;17(11):3789-94. doi: 10.1016/j.bmc.2009.04.046. Epub 
      2009 May 3.