New 2',6'-dimethyl-L-tyrosine (Dmt) opioid peptidomimetics based on the Aba-Gly scaffold. Development of unique mu-opioid receptor ligands.
The Aba-Gly scaffold, incorporated into Dmt-Tic ligands (H-Dmt-Tic-Gly-NH-CH2-Ph, H-Dmt-Tic-Gly-NH-Ph, H-Dmt-Tic-NH-CH2-Bid), exhibited mixed micro/delta or delta opioid receptor activities with micro agonism. Substitution of Tic by Aba-Gly coupled to -NH-CH2-Ph (1), -NH-Ph (2), or -Bid (Bid=1H-benzimidazole-2-yl) (3) shifted affinity (Ki(micro)=0.46, 1.48, and 19.9 nM, respectively), selectivity, and bioactivity to micro-opioid receptors. These compounds represent templates for a new class of lead opioid agonists that are easily synthesized and suitable for therapeutic pain relief.
Ballet
Steven
S
Department of Organic Chemistry, Vrije Universiteit Brussels, Pleinlaan 2, B-1050 Brussels, Belgium.
Salvadori
Severo
S
Trapella
Claudio
C
Bryant
Sharon D
SD
Jinsmaa
Yunden
Y
Lazarus
Lawrence H
LH
Negri
Lucia
L
Giannini
Elisa
E
Lattanzi
Roberta
R
Tourwé
Dirk
D
Balboni
Gianfranco
G
D000701:Analgesics, Opioid / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001552:Benzazepines / Q000138:chemical synthesis* / Q000494:pharmacology; D005998:Glycine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008024:Ligands; D018716:Molecular Mimicry; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000294:innervation / Q000502:physiology; D009197:Myenteric Plexus / Q000502:physiology; D010455:Peptides / Q000737:chemistry*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017465:Receptors, Opioid, delta / Q000378:metabolism; D017450:Receptors, Opioid, mu / Q000819:agonists*; D013329:Structure-Activity Relationship; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism
D000701:Analgesics, Opioid; D001552:Benzazepines; D008024:Ligands; D010455:Peptides; D017465:Receptors, Opioid, delta; D017450:Receptors, Opioid, mu; D005998:Glycine