Method of inhibiting opioid tolerance with chimeric hybrid analgesics

Abstract

The present invention provides a method of inhibiting the development of opioid tolerance using novel chimeric hybrid molecules containing an opioid moiety of chemically modified morphine ( 3 ) that binds to and activates the human mu (μ) opioid receptor, with the opioid moiety linked through a novel linker-hinge ( 4 ) to a substance P peptide fragment moiety ( 5 ) that binds to and activates the human substance P receptor. The hybrid alkaloid/peptide analgesics may be administered intrathecally, systemically or orally.

I claim:  
     
         1 . A method of inhibiting the development of opioid tolerance by clinically administering a chemically combination of a pharmacologically active form of substance p with morphine in a chimeric hybrid molecule wherein morphine, chemically modified and covalently linked through its 6′OH group, comprises a cyclic alkaloid moiety which binds as an agonist to a mammalian or human (μ) opioid receptor; and wherein a pharmacologically active C-mu terminal substance P fragment, chemically modified and covalently linked through its free NH2 group, comprises a peptide moiety which binds as an agonist to a mammalian/human substance p receptor; and wherein a compact, but flexible, molecular hinge covalently cross links morphine through its 6′OH group to the free NH2 group of the substance p receptor agonist moiety, so as to allow both the mu (μ) opioid receptor and the substance p receptor agonist moieties to activate their respective receptors simultaneously and independently.