Compositions and methods for controlling neuronal excitation
Embodiments of the technology described herein relate, at least in part, to methods of modulating the activity of a neuron by contacting the neuron with a photo-sensitive TrpA1 agonist and then illuminating the neuron with electromagnetic radiation. Also described herein are photo-sensitive TrpA1 agonists.
1. A method of modulating the activity of a neuron, the method comprising;
a) contacting the neuron with a compound of formula Ia or Ib:
wherein R 11 is hydrogen; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; substituted or unsubstituted, branched or unbranched acyl; substituted or unsubstituted, branched or unbranched aryl; substituted or unsubstituted, branched or unbranched heteroaryl; —C(═O)R B ; —CO 2 R B ; or —C(R B ) 3 ; wherein each occurrence of R B is independently hydrogen; halogen; a protecting group; aliphatic; heteroaliphatic; acyl; aryl moiety; heteroaryl; hydroxyl; aloxy; aryloxy; alkylthioxy; arylthioxy; amino; alkylamino; dialkylamino; heteroaryloxy; heteroarylthioxy; or alkylhalo;
R 12 , R 13 , and R 14 , are independently hydrogen; halogen; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; substituted or unsubstituted, branched or unbranched acyl; substituted or unsubstituted, branched or unbranched aryl; substituted or unsubstituted, branched or unbranched heteroaryl; —C(═O)R B ; —CO 2 R B ; -; —CN; —SCN; —SR B ; —SOR B ; —SO 2 R B ; —NO 2 ; —N(R B ) 2 ; —NHC(O)R B ; or —C(R B ) 3 ; wherein each occurrence of R B is independently hydrogen; halogen; a protecting group; aliphatic; heteroaliphatic; acyl; aryl moiety; heteroaryl; hydroxyl; aloxy; aryloxy; alkylthioxy; arylthioxy; amino; alkylamino; dialkylamino; heteroaryloxy; heteroarylthioxy; or alkylhalo;
R 15 is hydrogen;
Y 1 is O;
Y 2 is S;
X 1 is NH;
X 2 is NH or S; and
b) exposing the neuron to electromagnetic radiation comprising a wavelength of from about 300 nm to about 700 nm.
2. The method of claim 1 , wherein only neurons contacted with the compound and exposed to the electromagnetic radiation are activated.
3. The method of claim 1 , wherein the activity of the neuron is increased.
4. The method of claim 1 , wherein the functional output of the neuron is decreased.
5. The method of claim 1 , wherein the neuron is functionally ablated.
6. The method of claim 1 , wherein the neuron is ablated.
7. The method of claim 1 , wherein the neuron is a neuron of a subject in need of treatment for pain or inflammation.
8. The method of claim 7 , wherein the pain is neuropathic.
9. The method of claim 1 , wherein the subject has a spinal cord injury.
10. A method of performing deep brain stimulation, the method comprising:
a) contacting a neuron in the brain with a compound of formula Ia or Ib:
wherein R 11 is hydrogen; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; substituted or unsubstituted, branched or unbranched acyl; substituted or unsubstituted, branched or unbranched aryl; substituted or unsubstituted, branched or unbranched heteroaryl; —C(═O)R B ; —CO 2 R B ; or —C(R B ) 3 ; wherein each occurrence of R B is independently hydrogen; halogen; a protecting group; aliphatic; heteroaliphatic; acyl; aryl moiety; heteroaryl; hydroxyl; aloxy; aryloxy; alkylthioxy; arylthioxy; amino; alkylamino; dialkylamino; heteroaryloxy; heteroarylthioxy; or alkylhalo;
R 12 , R 13 , and R 14 , are independently hydrogen; halogen; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; substituted or unsubstituted, branched or unbranched acyl; substituted or unsubstituted, branched or unbranched aryl; substituted or unsubstituted, branched or unbranched heteroaryl; —C(═O)R B ; —CO 2 R B ; -; —CN; —SCN; —SR B ; —SOR B ; —SO 2 R B ; —NO 2 ; —N(R B ) 2 ; —NHC(O)R B ; or —C(R B ) 3 ; wherein each occurrence of R B is independently hydrogen; halogen; a protecting group; aliphatic; heteroaliphatic; acyl; aryl moiety; heteroaryl; hydroxyl; aloxy; aryloxy; alkylthioxy; arylthioxy; amino; alkylamino; dialkylamino; heteroaryloxy; heteroarylthioxy; or alkylhalo;
R 15 is hydrogen;
Y 1 is O;
Y 2 is S;
X 1 is NH;
X 2 is NH or S; and
b) exposing the neuron to electromagnetic radiation comprising a wavelength of from about 300 nm to about 700 nm.
11. The method of claim 1 , wherein the compound is selected from the group consisting of:
12. The method of claim 1 , wherein the electromagnetic radiation comprises a wavelength of from about 360 nm to about 450 nm.
13. The method of claim 1 , wherein the neuron comprises at least one TrpA1 channel.
14. The method of claim 1 , wherein R 13 is hydrogen; and wherein R 12 and R 14 are methyl.
15. The method of claim 1 , wherein R 11 is selected from methyl;