Identification of 7 Nicotinic Acetylcholine Receptor Agonists for their Assessment in Improving Cognition in Schizophrenia - Accounts in Drug Discovery Case Studies in Medicinal Chemistry - page 333

channels. The homo-pentameric a7 nAChR consists of five a7 subunits, each
providing an orthosteric binding site for its endogenous ligand, acetylcholine. 5
Numerous studies have established the importance of this class of ion
channels within the central nervous system (CNS), particularly its link to higher
functions such as memory, cognition, and sensory processing. 6 Receptors in the
homomeric a7 subtype are prevalent in the hippocampus and are thought to
modulate a variety of attention and cognitive processes. 7 Deficits in auditory
sensory processing are thought to lead to sensory overload and contribute to
attention and cognitive problems in a variety of CNS diseases, especially
schizophrenia. 8 Individuals with schizophrenia have decreased levels of a7
nAChRs as well as sensory gating deficits that can be corrected with nicotine;
analogous deficits in rodent models can also be restored with the a7 nAChR
partial agonist GTS-21. 9 Improvements in sensory gating have been shown to
correlate with improvements in cognitive performance in animal models and
schizophrenic patients, 10 suggesting that a selective a7 nAChR agonist may
play a role in treating schizophrenia. 11,12 Interest in a7 nAChR agonists has
greatly expanded during the past two decades, and many novel and selective
chemical entities have been identified. An extensive review of the medicinal
chemistry literature reveals that the majority of these ligands have been derived
from various aminoquinuclidine-containing scaffolds, 13 including such struc-
tures as spiro-oxazolidinones (AR-R17779), carbamates, ethers, and amides.
Our interest in this target began in 1998, when the few structures other than
anabasine and GTS-21 described in the literature were fairly weak and non-
selective for the a7 nAChR. Our goal was to discover and develop orally active
a7 nAChR agonists to treat cognitive deficits in schizophrenia or Alzheimer's
disease.

15.2 Identifying the Right Lead

15.2.1 High-throughput Screening to Identify High-quality Hits
When our program commenced, the short-term goals of the team focused on
the development of the reagents, assays, and technologies required to use the a7
nAChR as a drug target for a high-throughput screen (HTS). Consistent with
these goals, early synthetic efforts focused on the synthesis of known activators
of the a7 nAChR, such as anabasine, GTS-21, AR-R17779, and galanthamine
to aid in assay development and validation. These chemical tools were critical
in validating a robust fluorometric imaging plate reader-based screen (FLIPR;
Molecular Devices, Sunnyvale, CA) for an HTS using a chimeric surrogate for
the a7 nAChR (a7/5-HT 3 ) that joined the extracellular portion of the a7
nAChR with the transmembrane portion of the 5-HT 3 receptor, a serotonin-
gated ion channel closely related to nAChRs. 14 Quinuclidine amide 1
(Figure 15.1) was identified via this HTS as an agonist with weak ligand binding
anity (K i )ofthea7/5-HT 3 chimera, and was a known serotonin 5-HT 3
antagonist (K i ¼ 1 nM) typical of the quinuclidine amide 5-HT 3 inhibitor