Design of the Neurotensinergic Dipeptide Neuroleptic Drug Dilept

Abstract

An approach to the design of dipeptide neuroleptics free of extrapyramidal effects is described. Proceeding from an original hypothesis about the peptidergic mechanism of action of the atypical neuroleptic drug sulpiride and using the method of drug-based peptide synthesis, a peptide prototype of sulpiride — Pro-Tyr-NH₂ dipeptide — was obtained whose neuroleptic activity and the absence of cataleptogenic properties were revealed by tests on experimental animals. An analysis of the structures of known neuropeptides showed that the Pro-Tyr dipeptide sequence coincides with a Pro¹⁰-Tyr¹¹ fragment of the tridecapeptide neurotensin referred to in the literature as a neuropeptide with neuroleptic properties. Further design based on the obtained active dipeptide structure and the supposed bioactive β-rotational conformation of the neurotensin 8 – 13 sequence led to a group of new potential atypical neuroleptics, N-acylprolyltyrosines. The structure of these tripeptoid analogs of neurotensin contains an N-acyl group imitating the Leu¹³ side chain of neurotensin, which plays an important role in receptor binding. One of these compounds, N-caproyl-L-prolyl-L-tyrosine methyl ester, was named Dilept and chosen for more extensive pharmacological characterization as a potential antipsychotic agent. Preclinical investigations showed that Dilept is effective in doses 0.4 – 4.0 mg/kg (i.p.) and retains activity upon peroral administration. The drug is nontoxic and does not induce extrapyramidal disorders even when administered in amounts 1000 times higher than the effective dose.