Abstract: Nicotinic acetylcholine receptors (nAChRs) are ligand-gated ion channels that are activated by neurotransmitter acetylcholine for signaling, and they also respond to drugs including the nicotinic receptor agonist nicotine. The nAChRs can be classified into 5 muscle nAChR subtypes and 12 neuronal nAChR subtypes. Among the neuronal nAChR subtypes, α7 nAChR (also known as α7 receptor) that was first isolated and evaluated in 1990s from avian and rodents are homomeric pentamers widely distributed in the central nervous system (CNS) and periphery organs such as spleen and lymph nodes. The five identical α7 nAChR subunits are symmetrically organized around the central pore, and each subunit consists of a large amino-terminal extracellular domain (ECD), four transmembrane domains (TMD, TM1-TM4) and a cytoplasmic domain. In each homomeric α7 nAChR, there are 5 acetylcholine (ACh) binding sites within the ECD, which are located at the interface of each two subunites.
The α7 nAChR exhibits unique functional properties including: 1) fast activation and desensitization by agonists (in millisecond scale); 2) high calcium permeability (PCa / PNa ≈ 10); 3) selective inhibition by α-bungarotoxin (α-Btx) and methyllycaconitine (MLA). In the brain, α7 nAChRs are abundantly expressed in the regions underlying cognition and memory, such as hippocampus and frontal cortex. In neurons, the presynaptically localized α7 nAChRs are physiologically more important although they are widely localized in the synapses (both pre- and postsynaptically) and extra-synapses. Presynaptic α7 nAChRs play major role in facilitating glutamate release in the cerebellum, auditory cortex, hippocampus and many other brain areas. The impairment of α7 nAChR is implicated in cognitive deficits and neuropsychiatric disorders. Thus, enhancement of homomeric α7 nAChR function is considered to be a potential therapeutic strategy aimed at ameliorating cognitive deficits for neuropsychiatric disorders such as Alzheimer’s disease (AD) and schizophrenia. In this presentation, I will talk about our recent efforts in identification and pharmacological evaluation of novelα7 nAChR agonists and positive allosteric modulators (PAMs) for improvement of cognitive function.