To cite this article:
Topography of the neurotensin (NT)(8−9) binding site of human NT receptor-1 probed with NT(8–13) analogs
Article first published online: 20 MAR 2002
The Journal of Peptide Research
Volume 59, Issue 2, pages 55–61, February 2002
How to Cite
Lundquist IV, J.T., Büllesbach, E.E., Golden, P.L. and Dix, T.A. (2002), Topography of the neurotensin (NT)(8−9) binding site of human NT receptor-1 probed with NT(8–13) analogs. The Journal of Peptide Research, 59: 55–61. doi: 10.1046/j.1397-002x.2001.10946.x
Lundquist IV, J. T., Büllesbach, E. E., Golden, P. L. & Dix, T. A. Topography of the neurotensin (NT)(8−9) binding site of human NT receptor-1 probed with NT(8−13) analogs.
J. Peptide Res., 2002, 59, 55–61.
- Issue published online: 8 DEC 2008
- Article first published online: 20 MAR 2002
- Dates:Received 17 May 2001Revised 25 June 2001Accepted 30 September 2001
- amino acids;
- neurotensin receptor;
- non-natural amino acids;
Abstract: A series of neurotensin (NT)(8–13) analogs featuring substitution of the Arg8 and/or Arg9 residues with non-natural cationic amino acids was synthesized and evaluated for binding to the human NT receptor-1 (hNTR-1). The modifications were designed to probe specific steric and electrostatic requirements in the N-terminal cationic region of NT(8–13) for receptor binding as a general evaluation of the feasibility of incorporating minor structural changes into a peptide at a crucial polar receptor binding site. Many of the non-natural amino acids are more or less isosteric to Arg but more lipophilic as a result of addition of alkyl groups or through removal or replacement of NH character with methylene or methyl substituents, whereas others vary the distance between the cation and the α–amino acid carbon. Substitution of Arg8 with NG-alkylated Arg derivatives or homolysine (Hlys) maintained the subnanomolar affinity of NT(8–13) to the hNTR-1. Position 8 incorporation of Hlys produced the most favorable primary amine side-chain substitution to date. Moderate losses in affinity observed with position 9 substitutions were attributed to adverse steric effects. Doubly substituted [Hlys8, DAB9]NT(8–13), in which DAB is 2,4-diaminobutyric acid, was also prepared and tested as the shorter side-chain of DAB is known to be favored in position 9 of NT(8–13). This analog maintained 60% of NT(8–13) binding affinity making it the most favored des-guanidinium-containing analog known. These results demonstrate that adequate receptor binding affinity can be maintained over a structural range of Arg analogs, thus providing a range of peptides expected to exhibit altered pharmacokinetic properties. From the standpoint of the hNTR-1 cationic binding sites, these results help to map out the structural stringency inherent in the formation of a tight binding complex with NT(8–13) and related analogs.