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

• Published in: Journal of medicinal chemistry Vol. 41; no. 3; pp. 284 - 290
• Main Authors: Gudasheva, Tatiana A, Voronina, Tatiana A, Ostrovskaya, Rita U, Zaitseva, Natalya I, Bondarenko, Nina A, Briling, Vera K, Asmakova, Ludmila S, Rozantsev, Grigory G, Seredenin, Sergei B
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 29.01.1998; Amer Chemical Soc
• Subjects: Animals; Antipsychotic Agents - chemical synthesis; Antipsychotic Agents - pharmacology; Behavior, Animal - drug effects; Chemistry, Medicinal; Life Sciences & Biomedicine; Magnetic Resonance Spectroscopy; Male; Mice; Mice, Inbred C57BL; Neurotensin - analogs & derivatives; Pharmacology & Pharmacy; Rats; Science & Technology; Structure-Activity Relationship; Tyrosine - analogs & derivatives; Tyrosine - chemical synthesis; Tyrosine - pharmacology; NEUROLEPTIC ACTIVITY; SERIES; RECEPTORS; DERIVATIVES; PEPTIDE
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm970217c

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.