Synthesis and Evaluation of Compound Targeting α7 and β2 Subunits in Nicotinic Acetylcholinergic Receptor
2023
Karanveer Singh | Allyson Ngo | Oshini V. Keerthisinghe | Krystal K. Patel | Christopher Liang | Jogeshwar Mukherjee
Nicotinic acetylcholine receptors (nAChRs) are involved in various central nervous system functions and have also been implicated in several neurodegenerative disorders. The heteromeric &alpha:4&beta:2* and homomeric &alpha:7 are two major nAChR subtypes which have been studied in the brain using positron emission tomography (PET). Our comparative autoradiographic studies of the two receptor types in the mouse and rat brains show major differences in the thalamus (&alpha:4&beta:2* >:>: &alpha:7), hippocampus (&alpha:7 >:>: &alpha:4&beta:2*), and subiculum (&alpha:4&beta:2* >:>: &alpha:7). A relatively newer heteromeric &alpha:7&beta:2 nAChR subtype has been identified in the brain which may have a greater role in neurodegeneration. We report the development of KS7 (3-(2-(S)-azetidinylmethoxy)-5-(1,4-diaza-bicyclo[3.2.2]nonane)pyridine) which incorporates structural features of Nifzetidine (high affinity for &alpha:4&beta:2* nAChR) and ASEM (high affinity for &alpha:7 nAChR) in an effort to target &alpha:7 and &beta:2 subunits in &alpha:7&beta:2 nAChR. KS7 exhibited higher affinities (IC50 = 50 to 172 nM) for [3H]cytisine radiolabeled sites and weaker affinities (IC50 = 10 &mu:M) for [125I]-&alpha:-bungarotoxin radiolabeled rat brain sites in several brain regions. The weaker affinity of KS7 to &alpha:7 nAChR may suggest lack of binding at the &alpha:7 subunit of &alpha:7&beta:2 nAChR. A radiolabeled derivative of KS7 may be required to identify any specific binding to brain regions suggested to contain &alpha:7&beta:2 nAChR.
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