Mixed μ agonist/ δ antagonist opioid analgesics with reduced tolerance liabilities and uses thereof
An opioid narcotics used for the treatment of moderate-to-severe pain that primarily exert their analgesic effects through μ receptors. Although, traditional μ agonists can cause undesired side effects, including tolerance, addition of δ antagonists can attenuate said side effects. The present invention includes 4a,9-dihydroxy-7a-(hydroxymethyl)-3-methyl-2,3,4,4a,5,6-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7(7aH)-one (UMB 425) a 5,14-bridged morphinan-based orvinol precursor, along with analogs of morphine, dihydromorphine, hydromorphone, codeine, dihydrocodeine, hydrocodone and ethylmorphine. Although UMB 425 lacks δ-specific motifs, conformationally sampled pharmacophore models for μ and δ receptors predict it to have efficacy similar to morphine at μ receptors and similar to naltrexone at δ receptors, due to the compound sampling conformations in which the hydroxyl moiety interacts with the receptors similar to orvinols. UMB 425 exhibits a mixed μ agonist/δ antagonist profile as determined in receptor binding. UMB 425 has mixed μ agonist/δ antagonist properties in vitro that translate to reduced tolerance liabilities in vivo.
1. A chemical compound having formula UMB 425:
2. An opioid narcotic compound having a formula selected from the group consisting of Compound B and Compound C:
where R is hydrogen, methyl or ethyl and R 1 is selected from the group consisting of an alkoxy group, a halogen group, an alkylamino group, an amide group and an alkyl group;
where R is hydrogen or methyl and R 1 is selected from the group consisting of an alkoxy group, a halogen group, an alkylamino group, an amide group and an alkyl group.
3. The opioid narcotic compound of claim 2 , wherein the compound is Compound B.
4. The opioid narcotic compound of claim 2 , wherein the compound is Compound C.
5. A method of treating pain comprising administering to a patient in need thereof a therapeutically effective amount of the chemical compound having formula UMB 425 of claim 1 .
6. The method of treating pain of claim 5 wherein said pain is moderate-to-severe pain.
7. A method of treating pain comprising administering to a patient in need thereof a therapeutically effective amount of the chemical compound having the formula selected from the group consisting of Compound B and Compound C of claim 2 .
8. The method of treating pain of claim 7 wherein said pain is moderate-to-severe pain.
9. An opioid narcotic compound having a formula selected from the group consisting of Compound A and Compound D:
where R is methyl and R 1 is selected from the group consisting of an alkoxy group, a halogen group, an alkylamino group, and an amide group; and
where R is hydrogen or methyl and R 1 is selected from the group consisting of an alkoxy group, a halogen group, an alkylamino group, and an amide group.
10. The opioid narcotic compound of claim 9 , wherein the compound is Compound A.
11. The opioid narcotic compound of claim 9 , wherein the compound is Compound D.
12. A method of treating pain comprising administering to a patient in need thereof a therapeutically effective amount of the chemical compound having the formula selected from the group consisting of Compound A, and Compound D of claim 9 .
13. The method of treating pain of claim 12 wherein said pain is moderate-to-severe pain.