Endomorphin-2 with a beta-turn backbone constraint retains the potent micro-opioid receptor agonist properties.
The constitutional similarity with different secondary structure preference between the Aba-Gly and the spiro-Aba-Gly scaffolds were exploited to design the novel endomorphin-2 analogs Tyr-spiro-( R/ S)-Aba-Gly-Phe-NH(2) ( 1 and 2) and Tyr-( R/ S)-Aba-Gly-Phe-NH(2) ( 3 and 4). The ( R)-spiro analog 1 was found to be a potent and selective micro-opioid agonist/partial agonist ( K (imicro) = 29.3 nM, IC(50) = 50 nM, K(e) = 0.57). NMR experiments and molecular modeling indicated that its backbone adopts mainly a beta-turn in aqueous solution.
Institute of Biochemistry, Biological Research Center of the Hungarian Academy of Sciences, Temesvári krt. 62., H-6726 Szeged, Hungary. tomboly@brc.hu
Csaba
C
Tömböly
Steven
S
Ballet
Debby
D
Feytens
Katalin E
KE
Kövér
Attila
A
Borics
Sándor
S
Lovas
Mahmoud
M
Al-Khrasani
Zsuzsanna
Z
Fürst
Géza
G
Tóth
Sándor
S
Benyhe
Dirk
D
Tourwé
D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000737:chemistry; D017433:Protein Structure, Secondary; D017450:Receptors, Opioid, mu / Q000819:agonists*; D012996:Solutions; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D009842:Oligopeptides; D017450:Receptors, Opioid, mu; D012996:Solutions; C105294:endomorphin 2