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      Development of a potent and selective GPR7 (NPBW1) agonist: a systematic structure-activity study of neuropeptide B.

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          Abstract

          Neuropeptide B (NPB) has been recently identified as an endogenous ligand for GPR7 (NPBW1) and GPR8 (NPBW2) and has been shown to possess a relatively high selectivity for GPR7. In order to identify useful experimental tools to address physiological roles of GPR7, we synthesized a series of NPB analogs based on modification of an unbrominated form of 23 amino acids with amidated C-terminal, Br(-)NPB-23-NH(2). We confirmed that truncation of the N-terminal Trp residue resulted in almost complete loss of the binding affinity of NPB for GPR7 and GPR8, supporting the special importance of this residue for binding. Br(-)NPB-23-NH2 analogs in which each amino acid in positions 4, 5, 7, 8, 9, 10, 12 and 21 was replaced with alanine or glycine exhibited potent binding affinity comparable to the parent peptide. In contrast, replacement of Tyr(11) with alanine reduced the binding affinity for both GPR7 and GPR8 four fold. Of particular interest, several NPB analogs in which the consecutive amino acids from Pro4 to Val(13) were replaced with several units of 5-aminovaleric acid (Ava) linkers retained their potent affinity for GPR7. Furthermore, these Ava-substituted NPB analogs exhibited potent agonistic activities for GPR7 expressed in HEK293 cells. Among the Ava-substituted NPB analogs, analog 15 (Ava-5) and 17 (Ava-3) exhibited potency comparable to the parent peptide for GPR7 with significantly reduced activity for GPR8, resulting in high selectivity for GPR7. These highly potent and selective NPB analogs may be useful pharmacological tools to investigate the physiological and pharmacological roles of GPR7.

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          Author and article information

          Journal
          J. Pept. Sci.
          Journal of peptide science : an official publication of the European Peptide Society
          Wiley
          1075-2617
          1075-2617
          Jun 2007
          : 13
          : 6
          Affiliations
          [1 ] Department of Metabolic Disorder Research, Tsukuba Research Institute, Banyu Pharmaceutical Co., Ltd., Okubo 3, Tsukuba, Ibaraki 300-2611, Japan.
          Article
          10.1002/psc.855
          17486669
          0484ca2b-612e-4b71-a023-a4bddf3652d0
          History

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