Difunctional D-amino acid modified opioid peptide compound as well as synthesis method and application thereof

Abstract

The invention discloses a difunctional D-amino acid modified opioid peptide compound, a synthesis method of the compound and application of the series of analogues to preparation of analgesics. The synthesis method comprises the steps of synthesizing solid-phase carrier peptide resin; on the solid-phase carrier, sequentially inoculating corresponding amino acid according to the sequence from a C end to an N end of a polypeptide sequence; and performing peptide resin after treatment, cutting peptide, extracting peptide and performing preparation and purification. The synthesis method is simpleand convenient, easy to operate, short in condensation time, capable of perform large-scale synthesis and easy in purification. Sites, which are easily identified by enzyme and subjected to digestion,in a modified sequence are selectively replaced, high mu-opioid receptor can be maintained, the ability of resisting hydrolysis of enzyme in a living body can be obviously improved, the duration timeof analgesic activity and analgesic effect is prolonged, the bioavailability is effectively improved, and good pharmacological activity and potential clinical application value are achieved.

Description

technical field [0001] The invention belongs to the technical field of biomedicine, and specifically relates to a class of bifunctional D-amino acid modified opioid peptide compounds and a synthesis method and application thereof. Background technique [0002] Opioids (such as morphine, codeine, etc.), have high binding ability and agonistic activity to opioid receptors, and exhibit strong analgesic activity. They are clinically used to relieve severe pain (such as cancer pain or surgical pain). Posterior Pain) the most effective analgesic drug (J. Pain Res. 2014 7 589). However, the potent analgesic effects of such opioids are often accompanied by many unpleasant side effects, such as sedation, physical dependence, tolerance, respiratory depression, constipation, and reward-seeking behavior. [0003] Opioids produce clinical analgesic effects through the interaction with the opioid receptor system. There are three types of classical opioid receptors, namely μ-opioid recep...

AI Technical Summary

Problems solved by technology

The structure-effect relationship study of endomorphin found that using D-amino acids (D-Tyr, D-Pro, D-Trp and D-Phe) to modify different sites of endomorphin-1 or endomorphin-2, Binding of endomorphin analogues to opioid receptors has a largely negative effect, especially when D-Pro 2 L-Pro Replacement Endomorphin-1 2 After that, the resulting new compound basically loses its ability to bind to μ-opioid receptors (Biophys J, 2000, 78, 590–599; Biochem Biophys Res Commun, 2000, 276, 7–11)

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