Sigma-1 receptor ligands and methods of use
The invention provides compounds of formula I and compositions thereof. The invention further provides methods of using the compounds and compositions. The compounds of the invention can provide high affinity binding to sigma-1 receptors in a mammal. The compounds can exhibit selectivity for the sigma-1 receptor over the sigma-2 receptor. The compounds and compositions of the invention can also be used to treat conditions that involve the sigma-1 receptor, such as addiction, cardiovascular conditions, and cancer, for example, cancer of the breast, lung, prostate, ovarian, colorectal, or the CNS.
1. A compound of formula II:
wherein
R 1 is (C 10 -C 17 )alkyl and R 2 is H; or
R 1 is para-aminobenzyl and R 2 is propyl;
or a salt thereof.
2. The compound of claim 1 wherein the σ-1 K D is about 6 nM or less.
3. The compound of claim 1 wherein the compound exhibits selectivity for the σ-1 receptor over the σ-2 receptor and the σ-2 Ki:σ-1 Ki ratio is about 0.4 or less.
4. The compound of claim 1 wherein the compound exhibits selectivity for the σ-2 receptor over the σ-1 receptor and the σ-2 Ki:σ-1 Ki ratio is at least about 10.
5. The compound of claim 1 wherein R 2 is H.
6. The compound of claim 1 wherein the compound is:
7. The compound of claim 1 wherein the compound is:
8. A method of binding a sigma-1 receptor in a mammal comprising administering to the mammal an effective amount of a compound of claim 1 .
9. A method of inhibiting cancer cell growth comprising contacting the cell with an effective inhibitory amount of a compound of claim 7 , so that the growth or replication of the cancer cell is inhibited, wherein the cancer cell is a breast cancer cell.
10. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable diluent or carrier.
11. A pharmaceutical composition comprising a compound of claim 5 and a pharmaceutically acceptable diluent or carrier.
12. A pharmaceutical composition comprising a compound of claim 6 and a pharmaceutically acceptable diluent or carrier.
13. A pharmaceutical composition comprising a compound of claim 7 and a pharmaceutically acceptable diluent or carrier.