Design of N-Acylprolyltyrosine “Tripeptoid” Analogues of Neurotensin as Potential Atypical Antipsychotic Agents

Abstract

A series of N-acylprolyltyrosine amides was designed as tripeptoid analogues of neurotensin. The substituted dipeptides were tested in vivo for antidopamine activity by their ability to inhibit the apomorphine-induced climbing in mice and the dopamine-induced extrapolatory behavior impairment in rats. The N-acylprolyltyrosine amides structure-activity relationships have indicated the size of the N-acyl group and the configuration of amino acids that are important for the activity. We found that the bioactivity has been increased dramatically when the n-hydrocarbon chain on the N-acyl group was increased from four to five carbon atoms. The activity seems to reside exclusively in the L-Tyr diastereomers. All of the compounds tested were inactive in the cataleptogenic action and did not exhibit the acute toxicity even at doses 500-1000 times higher than ED50 in climbing test. On this basis, the N-acylprolyltyrosine amides could potentially be a novel class of atypical antipsychotic agents.

Design of the Neurotensinergic Dipeptide Neuroleptic Drug Dilept

“…In these compounds, the N-acyl radical simulates the side chain of a third amino acid residue (Leu 13 ), which is remote in the peptide chain but spatially close to Pro 10 [15]. It was found that the introduction of N-acyl radicals in no case decreased, but sometimes increased the activity of obtained compound in the apomorphine-induced verticalization test (Table 4).…”

“…N-Caproyl-L-prolyl-L-tyrosine, the most active tripeptoid analog of neurotensin, was used to study the dependence of the neuroleptic activity on the nature of C-substitution [15]. In the series of acid -ester -amide -alkylamide, all compounds were active (Table 5), although the pharmacological activity of acid and substituted amide was less pronounced than of ether and unsubstituted amide.…”

Permeability of the Blood-Brain Barrier for Dilept and Its Active Metabolite

“…The drug exhibited antipsychotic effects in experiments [2,5]. Because of metabolic instability and low bioavailability of neuropsychotropic drugs of peptidergic structure, it is essential to study their penetration through the blood-brain barrier (BBB) and delivery to the target organ (brain) for realization of their effects in CNS.…”

Developing chromatography-mass spectrometry techniques for quantitative determination of the new original neuroleptic drug dilept

“…The dipeptide was identical to the Pro 10 -Tyr 11 fragment of neurotensin. The structure of the peptide analog of sulpiride was modified taking into account the assumption of biological activity for the â-turn conformation of neurotensin, the center of which contains the Pro 10 -Tyr 11 fragment, by adding an N-caproyl radical, which imitates the side radical of Leu 13 in neurotensin that is situated close to the proline [1]. Experiments established the neuroleptic activity of the resulting methyl ester of N-caproyl-L-prolyl-L-tyrosine (dilept) at doses of 0.4 -4.0 mg/kg for i.p.…”