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Neurotensin Receptor Agonists and Antagonists for Schizophrenia

To the Editor: For nearly three decades, researchers have hypothesized that neurotensin is an endogenous neuroleptic (1). This idea is based on animal behavioral studies that showed marked similarities between antipsychotic drugs and neurotensin, which needs to be directly injected into the brain to cause its CNS effects. In fact, in some behavioral paradigms, neurotensin acts like an atypical antipsychotic drug (2). More recently, researchers showed that antipsychotic drugs rapidly increase the expression and release of neurotensin. Therefore, it has been suggested that the therapeutic effects of antipsychotic drugs are mediated by endogenous neurotensin (3). Indeed, in rodent models that are predictive of antipsychotic activity, a neurotensin receptor agonist (NT69L) that we have under development and that is able to cross the blood-brain barrier acts like an atypical antipsychotic drug (4, 5). Therefore, we were not surprised to learn from the article by Herbert Y. Meltzer, M.D., et al. (6) that a neurotensin receptor antagonist, SR48692, had no efficacy in treating schizophrenia.

Many different research groups, both in industry and academia, over more than two decades have been unable to develop a nonpeptide neurotensin agonist. The lack of availability of nonpeptide agonists of neurotensin receptors, however, should not cause us to ignore the preponderance of evidence favoring a therapeutic role for neurotensin receptor agonists, rather than neurotensin receptor antagonists, in schizophrenia. Our compound, containing a novel amino acid, a regio-isomer of L-tryptophan (7), is a peptide that is resistant to degradation by peptidases and is thus available to enter the brain after it is injected outside the brain. This compound is in preclinical toxicology testing (with support from the Stanley Foundation) for planned human studies. Future resources should be directed toward bringing neurotensin receptor agonist compounds into human clinical trials.

References

1. Nemeroff CB: Neurotensin: perchance an endogenous neuroleptic? Biol Psychiatry 1980; 15:283–302[Medline]
2. Jolicoeur FB, Gagne MA, Rivest R, Drumheller A, St-Pierre S: Atypical neuroleptic-like behavioral effects of neurotensin. Brain Res Bull 1993; 32:487–491[CrossRef][Medline]
3. Kinkead B, Binder EB, Nemeroff CB: Does neurotensin mediate the effects of antipsychotic drugs? Biol Psychiatry 1999; 46:340–351[CrossRef][Medline]
4. Cusack B, Boules M, Tyler BM, Fauq A, McCormick DJ, Richelson E: Effects of a novel neurotensin peptide analog given extracranially on CNS behaviors mediated by apomorphine and haloperidol. Brain Res 2000; 856:48–54[CrossRef][Medline]
5. Shilling PD, Melendez G, Priebe K, Richelson E, Feifel D: Neurotensin agonists block the prepulse inhibition deficits produced by a 5-HT(2A) and an alpha(1) agonist. Psychopharmacology (Berl) 2004; 175:353–359[Medline]
6. Meltzer HY, Arvanitis L, Bauer D, Rein W (Meta-Trial Study Group): Placebo-controlled evaluation of four novel compounds for the treatment of schizophrenia and schizoaffective disorder. Am J Psychiatry 2004; 161:975–984[Abstract/Free Full Text]
7. Fauq AH, Hong F, Cusack B, Tyler BM, Pang Y-P, Richelson E: Synthesis of (2S)-2-amino-3-(1H–4-indolyl)propanoic acid, a novel tryptophan analog for structural modification of bioactive peptides. Tetrahedron Asymmetry 1998; 9:4127–4134[CrossRef]

Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Email this article to a Colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to My Articles & Searches Download to citation manager Citing Articles via Google Scholar Articles by RICHELSON, E. Articles by BOULES, M. M. Search for Related Content PubMed Citation Articles by RICHELSON, E. Articles by BOULES, M. M. Schizophrenia Spectrum Disorders Other Somatic Therapy

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