N-substituted derivatives of morphinan and uses thereof
View Patent ↗The invention is based in part on the discovery that nonselective κ agonists that possess μ receptor-mediated effects in addition to their κ agonist effects can decrease cocaine self-administration more effectively and with fewer undesirable side effects than can highly selective κ agonists. The invention includes a number of new compounds having both nonselective κ opioid receptor agonist activity and additional activity at μ opioid receptors. These compounds are useful for the treatment of cocaine abuse, and can also be radiolabeled for use as imaging agents, e.g., the N-fluoroalkyl and iodoalkyl derivatives can be used, respectively, for positron emission tomography (PET) and single photon computed tomography (SPECT) brain imaging.
1. A compound of Formula I,
wherein R is 3-fluoropropyl (3); 2-ethoxyethyl (5); 2-methoxyethyl (6); 3,3,3-trifluoropropyl (10); 3-cyanopropyl (12); (2-furyl)methyl (22); 3-(2-thienyl)-3-oxo-propyl (26); 3-(2-furyl)-3-oxo-propyl (28); 3-(2-thienyl)-3-hydroxy-propyl (29); 3-(2-furyl)-3-hydroxy-propyl (31); 3-idoprop-(2E)-enyl (34); or 3-idoprop-(2Z)-enyl (35); 3-(tri-n-butylstannyl)-prop-(2E)-enyl (32); 3-(tri-n-butylstannyl)-prop-(2Z)-enyl (33); or a salt thereof.
2. The compound of claim 1 , wherein R is 3, 5, 6, 10, 12, 26, 28, 29, 31, 34, or 35, or a salt thereof.
3. The compound of claim 2 , wherein R is 3.
4. The compound of claim 2 , wherein R is 5.
5. The compound of claim 2 , wherein R is 6.
6. The compound of claim 2 , wherein R is 10.
7. The compound of claim 2 , wherein R is 12.
8. The compound of claim 2 , wherein R is 34.
9. The compound of claim 1 , wherein R is 35.
10. A pharmaceutical formulation comprising the compound of claim 1 , and a physiologically acceptable excipient.
11. A pharmaceutical formulation comprising the compound of claim 2 , and a physiologically acceptable excipient.
12. A method of single-photon computed tomography (SPECT) imaging of opioid receptors in a subject, the method comprising:
obtaining a compound of claim 1 and labeling the compound with a radioactive label,
administering the labeled compound to the subject; and
obtaining scans with a SPECT camera to image the opioid receptors.
13. The method of claim 12 , wherein the radioactive label is 123 I.
14. The method of claim 12 , wherein R is 34.
15. The method of claim 12 , wherein R is 35.
16. A SPECT imaging reagent comprising a 123 I-labeled compound of Formula I,
wherein R is 123 I-labeled 3-iodoprop-(2E)-enyl (34) or 3-idoprop-(2Z)-enyl (35).
17. A method of positron emission tomography (PET) imaging of brain opioid receptors in a subject, the method comprising:
obtaining a compound of claim 1 and labeling the compound with a radioactive label;
administering the labeled compound to the subject; and
obtaining brain scans with a PET camera to image the opioid receptors.
18. The method of claim 17 , wherein the radioactive label is 18 F.
19. The method of claim 17 , wherein R is 3.
20. The method of claim 17 , wherein R is 10.
21. A PET imaging reagent comprising an 18 F-labeled compound of Formula I,
wherein R is 18 F-labeled 3-fluoropropyl (3) or 3,3,3-trifluoropropyl (10).
22. A method of treating a patient addicted to cocaine, the method comprising administering to the patient an effective amount of a compound of claim 1 or one or more compounds of Formula I,
wherein R is 2-methylpropyl (4); 2-propenyl (8); 2-propynyl (9); 2-cyanoethyl (11).
23. The method of claim 22 , wherein R is 3, 5, 6, 10, 12, 26, 28, 29, 31, 34, or 35.
24. The method of claim 22 , wherein R is 4, 8, 9, or 11.
25. The method of claim 22 , wherein R is 3, 9, or 34.