Molecular design, synthesis and neuroleptic activity of dipeptide analogs of sulpride

The article is an overview of author’s data obtained in the framework of the project “The Creation of dipeptide preparations” at the V.V. Zakusov Institute of Pharmacology, Moscow, Russia. Advantages of dipeptides over longer peptides consist in that they are orally active owing to higher sta-bility and ability to penetrate biological barriers due to the presence of specific ATP–dependent trans-porters in enterocytes and blood-brain barrier. Two original approaches for dipeptide drugs design have been developed. Both of them are based on the idea of a leading role of central dipeptide fragment of the peptide chain beta-turn in the peptide-receptor interaction. The first approach, named “peptide drug-based design” represents the transformation of known nonpeptide drug into its dipeptide topological analog. The latter usually corresponds to a beta-turn of some regulatory peptide. The second approach represents the design of tripeptoide mimetic of the beta-turn of regulatory peptide or protein. The results of the studies, which led to the discovery of endogenous prototypes of the known non-peptide drugs piracetam and sulpiride, are presented herein. The paper discusses the process, based on the above-mentioned principles, that was used in designing of nontoxic, orally available, highly effective dipeptide drugs: nootropic noopept, dipeptide analog of piracetam; antipsychotic dilept, neurotensin tripeptoid analog; selective anxiolytic GB-115, tripeptoid analog of CCK-4, and potential neuroprotector GK-2, homodimeric dipeptide analog of NGF.

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“…The L-Pro-L-Tyr-NH 2 dipeptide demonstrated the neuroleptic-like activity i.p. in doses 10 times lower than Sulpiride [39].…”

Section: Dilept a Dipeptide Neurolepticmentioning

confidence: 99%

Novel Technologies for Dipeptide Drugs Design and their Implantation

Gudasheva

Ostrovskaya

Середенин

2018

CPD

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“…As is known, sulpiride predominantly blocks D 2 and (to a lower extent) D 3 and D 4 dopamine receptors, while not interacting with adrenergic, cholinergic, GABA-ergic, and serotonin receptors [7]. Taking these data into account, it was suggested that the antipsychotic effect of sulpiride could be related not only to the blocking of dopamine receptors, but to the possible peptidergic modulant mechanism as well [8].…”

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confidence: 96%

“…Besides the structural similarity, additional evidence for the peptidergic mechanism of sulpiride action is provided by the U-shaped dose -activity dependence [8], which is typical of most neuropeptides and reflects their neuromodulating properties.…”

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confidence: 99%

“…In order to verify this hypothesis, we have synthesized prolyltyrosine amide [8] as the simplest peptide analog of sulpiride. The neuroleptic activity of the obtained peptide was determined using the classical tests for inhibition of the apomorphine-induced verticalization in mice and the extrapolated avoidance of extremal situation against the background of madopar (L-DOPA + benserazide) in rats.…”

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confidence: 99%

“…Therefore, only the configuration of the tyrosine res-idue is important for manifestations of the neuroleptic activity of Pro-Tyr-NH 2 . As for the influence of the nature of amino acid residues in the simplest peptide analog of sulpiride, the replacement of proline by glycine (Gly-L-Tyr-NH 2 , where the glycine residue can be considered as the general fragment of natural amino acids deprived of side radicals), leads to the loss of neuroleptic activity [8]. This result is indicative of the participation of the side radical of proline in interactions with the anticipated receptor.…”

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confidence: 99%

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Design of the Neurotensinergic Dipeptide Neuroleptic Drug Dilept

Gudasheva

Зайцева

2005

Pharm Chem J

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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-NH 2 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 Pro 10 -Tyr 11 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 b-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 Leu 13 side chain of neurotensin, which plays an important role in receptor binding. One of these compounds, N-caproyl-Lprolyl-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. 230 0091-150X/05/3905-0230

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Theoretical grounds and technologies for dipeptide drug development

Gudasheva

2015

Russ Chem Bull

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Molecular design, synthesis and neuroleptic activity of dipeptide analogs of sulpride

Cited by 5 publications

References 9 publications

Novel Technologies for Dipeptide Drugs Design and their Implantation

Novel Technologies for Dipeptide Drugs Design and their Implantation

Design of the Neurotensinergic Dipeptide Neuroleptic Drug Dilept

Theoretical grounds and technologies for dipeptide drug development

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