The a7 nicotinic acetylcholine receptor (nAChR) is currently a drug target for Alzheimer's disease, schizophrenia, and inflammatory disorders. Traditionally, the function of the a7 receptor was linked to its ion channel activity; however growing evidence supports a metabotropic function that may modulate inflammatory response in non-neuronal cells. We introduce the term silent agonist to describe receptor ligands that are competitive antagonists, are not agonists on their own in the sense of ion channel activity, but place the receptor in a desensitized state that can be revealed in the presence of type II positive allosteric modulator (PAM). We have identified three structurally unique groups of silent agonist pharmacophores. One group is exemplified by benzylidene anabaseine type molecules, the second group features bulky quaternary alkyl ammonium compounds, and the third group is represented by newly designed and synthesized compounds KC-1, KC-5, KC-7. When tested in Xenopus oocytes, the compounds showed no response on their own but when co-applied at 100 �M with 10 �M PNU-120596, the net charge response relative to 60 �M ACh was 18, 12, and 21-fold higher for KC-1, KC-5, KC-7, respectively). Because these molecules convert the a7 nAChR from a resting state selectively into a desensitized state that can be probed by type II PAM, they are of interest as a tool to study the functions of the a7 nAChR that do not involve ion conducting states, and may constitute a new alternative for the development of a7 nAChR therapeutics.

Silent agonists for alpha7 nicotinic acetylcholine receptor

246th National Meeting (2013)

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