Pharmacological and biochemical profiles of unique neurotensin 8-13 analogs exhibiting species selectivity, stereoselectivity, and superagonism

B. Cusack, Daniel J Mc Cormick, Yuan-Ping Pang, T. Souder, R. Garcia, A. Fauq, E. Richelson

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Abstract

Recently, the rat neurotensin receptor and the two human neurotensin receptor clones (differing by one amino acid residue) have been isolated. We present results with 33 newly synthesized neurotensin analogs. We have evaluated their binding potency at the three neurotensin receptor clones by determining equilibrium dissociation constants and coupling to phosphatidylinositol turnover. Our work focused on position 8 and 9 substitutions as well as position 11 of the neurotensin hexamer NT8-13. The results presented include: 1) the development of a compound that is species selective, with a binding potency at the rat receptor that is 20-fold more potent than at the human receptor; 2) the development of a pair of stereoselective compounds with the L-isomer exhibiting 190-700-fold more potency than the D-isomer; and 3) the development of an agonist that has a K(d) of 0.3 and 0.2 nM at the human and rat neurotensin receptor, respectively, ranking it as among the most potent tested. Also, we present the first evidence that 1) the effect of pi electrons at position 11 (L-Tyr) are important for binding to the neurotensin receptor, and 2) the length of the side chain on position 9 (L-Arg) changes binding potency.

Original languageEnglish (US)
Pages (from-to)18359-18366
Number of pages8
JournalJournal of Biological Chemistry
Volume270
Issue number31
DOIs
StatePublished - 1995

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neurotensin (8-13)
Neurotensin Receptors
Stereoselectivity
Pharmacology
Rats
Neurotensin
Isomers
Clone Cells
Phosphatidylinositols
Substitution reactions
Electrons
Amino Acids

ASJC Scopus subject areas

  • Biochemistry

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Pharmacological and biochemical profiles of unique neurotensin 8-13 analogs exhibiting species selectivity, stereoselectivity, and superagonism. / Cusack, B.; Mc Cormick, Daniel J; Pang, Yuan-Ping; Souder, T.; Garcia, R.; Fauq, A.; Richelson, E.

In: Journal of Biological Chemistry, Vol. 270, No. 31, 1995, p. 18359-18366.

Research output: Contribution to journalArticle

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AU - Garcia, R.

AU - Fauq, A.

AU - Richelson, E.

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