N,N diethyl-N'phenylpiperazine alpha 7 and alpha 9 nicotinic acetylcholine receptor agonists and antagonists
Provided are embodiments of para-substituted 1,1-dialkyl-4-phenylpiperazin-1-ium iodides advantageous for modulating inflammation that have been synthesized and their electrophysiology activities for α9, α9α10, and α7 nAChRs compared. The para position contained alkyl or aryl amides, or heterocyclic isosteres for the amide, and the alkyl groups were varied at the ammonium piperazine nitrogen to see if compensatory changes in size at this position of the molecule impacted function. The compounds were characterized with two-electrode voltage-clamp measurements on Xenopus oocytes expressing nAChRs. General, the compounds were more potent for α9-containing receptors than for α7, and the majority were either full or strong partial agonists for α9-containing nAChR.
1. A method of treating a disease or disorder modulated by nicotinic acetylcholine receptor (nAChR) function in a subject, the method comprising administering a pharmaceutical composition comprising
a para-substituted 1,1-dialkyl-4-phenylpiperazin-1-ium having the formula:
wherein:
R 1 is a —CO—R 2 group, an oxazole, a pyrazole, or a pyrrole;
R 2 is a pyrrolidine group or an —NH—R 3 group;
R 3 is an alkyl group, an aryl group, a saturated heterocyclic group, a substituted saturated heterocyclic group, an unsaturated heterocyclic group, a substituted unsaturated heterocyclic group, a pyridine, a substituted pyridine group, or a substituted phenyl group; and
R 4 and R 5 are each independently a methyl group or an ethyl group, or a salt thereof to the subject.
2. The method of claim 1 , wherein the nAChR is an α9 nAChR, an α9α10 nAChR, or an α7 nAChR.
3. The method of claim 1 , wherein the disease or disorder is a nervous system disorder or a hearing disorder.
4. The method of claim 3 , wherein the nervous system disorder is Alzheimer's disease, schizophrenia, depression, attention deficit hyperactivity disorder (ADHD), tobacco addiction, chronic pain, Parkinson's disease, or any combination thereof.
5. The method of claim 3 , wherein the hearing disorder is noise-induced hearing loss, vertigo, tinnitus, or any combination thereof.
6. The method of claim 1 , wherein the para-substituted 1,1-dialkyl-4-phenylpiperazin-1-ium is selected from the group consisting of the formulae:
or a salt thereof.
7. The method of claim 1 , wherein the salt is an iodide.
8. The method of claim 1 , wherein the pharmaceutical composition further comprises at least one pharmaceutically acceptable carrier.
9. The method of claim 1 , wherein the pharmaceutically acceptable carrier comprises a diluent, an adjuvants, a vehicle, a non-toxic filler, an encapsulating material, or any combination thereof.
10. The method of claim 2 , wherein the nAChR is an α9 nAChR or an α9α10 nAChR and the compound is selected from
11. The method of claim 2 , wherein the nAChR is an α9 nAChR or an α9α10 nAChR and the compound is
12. The method of claim 2 , wherein the compound has an i max of greater than or equal to about 1.13 for the α9 nAChR.
13. The method of claim 2 , wherein the compound has an EC 50 of greater than or equal to about 0.38 for the α9 nAChR.
14. The method of claim 1 , wherein the compound or salt thereof is administered orally.