Sökning: onr:"swepub:oai:gup.ub.gu.se/129421" >
Disulfide Cyclized ...
Disulfide Cyclized Tripeptide Analogues of Angiotensin IV as Potent and Selective Inhibitors of Insulin-Regulated Aminopeptidase (IRAP)
-
Andersson, Hanna (författare)
-
Demaegdt, H (författare)
-
Vauquelin, G (författare)
-
visa fler...
-
Lindeberg, G (författare)
-
Karlén, A (författare)
-
Hallberg, M (författare)
-
- Erdelyi, Mate, 1975 (författare)
- Gothenburg University,Göteborgs universitet,Institutionen för kemi,Department of Chemistry
-
Hallberg, Anders (författare)
-
visa färre...
-
(creator_code:org_t)
- 2010
- 2010
- Engelska.
-
Ingår i: Journal of Medicinal Chemistry. - 0022-2623. ; 53, s. 8059-8071
- Relaterad länk:
-
https://gup.ub.gu.se...
Abstract
Ämnesord
Stäng
- The insulin-regulated aminopeptidase (IRAP) localized in areas of the brain associated with memory and learning is emerging as a new promising therapeutic target for the treatment of memory dysfunctions. The angiotensin II metabolite angiotensin IV (Ang IV, Val1-Tyr2-Ile3-His4-Pro5-Phe6) binds with high affinity to IRAP and inhibits this aminopeptidase (Ki = 62.4 nM). Furthermore, Ang IV has been demonstrated to enhance cognition in animal models and is believed to play an important role in cognitive processes. It is herein reported that displacement of the C-terminal tripeptide His4-Pro5-Phe6 with a phenylacetic acid functionality combined with a constrained macrocyclic system in the N-terminal affords potent IRAP inhibitors that are less peptidic in character than the hexapeptide Ang IV. Configurational analysis of three pairs of diastereomeric Ang IV analogues was performed using a combination of solution NMR spectroscopic methods, Monte Carlo conformational searches, and NAMFIS calculations. The compounds encompassing l-amino acids only (4, 8, and 12) showed significantly higher bioactivity compared to their lld-epimers (5, 9, and 13). The best inhibitors in the series, compounds 8 and 12, incorporating a 13- and 14-membered disulfide ring system, respectively, and both with a β3-homotyrosine residue (β3hTyr) replacing Tyr2, exhibit Ki values of 3.3 and 5.2 nM, respectively.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Läkemedelskemi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Medicinal Chemistry (hsv//eng)
- NATURVETENSKAP -- Kemi -- Organisk kemi (hsv//swe)
- NATURAL SCIENCES -- Chemical Sciences -- Organic Chemistry (hsv//eng)
- NATURVETENSKAP -- Kemi -- Fysikalisk kemi (hsv//swe)
- NATURAL SCIENCES -- Chemical Sciences -- Physical Chemistry (hsv//eng)
Nyckelord
- angiotensin
- IRAP
- NMR
- peptidomimetics
Publikations- och innehållstyp
- ref (ämneskategori)
- art (ämneskategori)
Hitta via bibliotek
Till lärosätets databas