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.