Neuromedin B receptor (NMB-R, BB1) antagonist selectively blocks NMB-suppressed glucose intake in vivo. It is also a potent urotensin II receptor antagonist and displays affinity for somatostatin and µ-opioid receptors 1.
BIM-23127 is a D-amino-acid substituted cyclo-somatostatin octapeptide analog that shares structural similarity with SB-710411, which functions as a competitive antagonist of the rat UT (rUT) receptor in the rat aorta and a full agonist at the recombinant hUT receptor 2.
It was discovered and reported by Orbuch et al., in 1993, that certain substituted somatostatin (SS) analogues selectively antagonized the BB1 receptor compared to the BB2 receptor 3. The most potent analogue was cyclo-SS-octa [D-Nal-Cys-Tyr- D-Trp-Lys-Val-Cys-Nal-NH2], which had a 100-fold higher affinity for the BB1 receptor than the BB2 receptor (Ki -230 vs. 3000 nM). Unfortunately this analogue also interacted with high affinity with somatostatin receptors (IC50-0.80 nM) and mu opioid receptors (IC50-430 nM). Substitution of an ornithine for Lys greatly reduced the affinity for somatostatin receptors, and a related analogue, (BIM-23127), [D-Nal-Cys-Tyr- D-Trp-Orn-Val-Cys-Nal-NH2] inhibited NMB cell signaling in rat BB1 receptor transfected Rat-1 cells and selectively reversed NMB feeding suppression, but had no effect on the action of GRP. However, a recent study reports BIM-23127 also functions as a receptor antagonist of both human and rat urotensin-II receptors limiting its utility. Peptoid antagonists of BB1 have been described including PD 165929 and PD 168368, which have high affinity and selectivity for BB1. In a detailed comparison of bombesin receptors from different species, PD 168368 was found to have a similar high affinity (Ki-15-45 nM) for BB1 receptors from each species, a 30- to 60-fold lower affinity for the BB2 receptor from different species. It also inhibited NMB-stimulated cellular signaling in a competitive manner as well as inhibiting NMB-induced proliferation of rat C6 glioblastoma cells and NMB stimulation of NCI-H1299 lung cancer cell proliferation 1.
BIM-23127: D-Nal-cyclo[Cys-Tyr-D-Trp-Orn-Val-Cys]-Nal-NH2.It is a D-amino-acid substituted cyclo-somatostatin octapeptide analog.
Mode of Action
BIM-23127 blocks NMB function by competitively binding to the NMB receptor2.
This selective NMB receptor antagonist completely blocked suppression of food intake produced by NMB but not by neuromedin C. This result suggested an independent role for NMB receptors in suppression of food intake by bombesin-like peptides and and demonstrated the utility of this group of antagonists for in vivo experiments4. Endogenous BN-like peptides, NMB and gastrin releasing peptides, have some roles for the modulation of learning and memory, and suggest that NMB/NMB-R pathway may also be involved in the memory acquisition and modulation as well as GRP/GRP-R pathway. NMB receptor antagonists have been used to provide an insight into these studies5. Both GRP-10 and NMB evoked concentration-dependent contractions in circular strips of esophagus and fundus and in longitudinal strips of the duodenum. These contractions were tetrodotoxin and atropine-resistant. The potency of NMB in esophageal strips was 33 times higher than that of GRP-10. In esophageal muscle NMB-preferring receptor antagonists inhibited the contractile activity of bombesin-like peptides6.
1. Jensen RT, Battey JF, Spindel ER, Benya RV. (2008). International Union of Pharmacology. LXVIII. Mammalian Bombesin Receptors: Nomenclature, distribution, pharmacology, signaling and functions in normal and disease states. Pharmacol Rev., 60(1):1–42.
2. Herold CL, Behm DJ, Buckley PT, Foley JJ, Wixted WE, Sarau HM, Douglas SA.(2003). The neuromedin B receptor antagonist, BIM-23127, is a potent antagonist at human and rat urotensin-II receptors. Br J Pharm., 139:203–207.
3. Orbuch M, Taylor JE, Coy DH, Mrozinski JE Jr, Mantey SA, Battey JF, Moreau JP, Jensen R(1993). Discovery of a novel class of neuromedin B receptor antagonists, substituted somatostatin analogues. Mol Pharmacol., 44(4):841-850.
4. Ladenheim EE, Taylor JE, Coy DH, Moran TH.(1994). Blockade of feeding inhibition by neuromedin B using a selective receptor antagonist. Eur.J.Pharmacol., 271(1):7-9.
5. Santo-Yamada Y, Yamada K, Wada E, Goto Y, Wada K. (2003). Blockade of bombesin-like peptide receptors impairs inhibitory avoidance learning in mice. Neurosci.Lett., 340(1):65-68.
6. Milusheva EA, Kortezova NI, Mizhorkova ZN, Papasova M, Coy DH, Bálint A, Vizi ES, Varga G. (1998). Role of Different Bombesin Receptor Subtypes Mediating Contractile Activity in Cat Upper Gastrointestinal Tract. Peptides, 19(3):549-56.
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