From the Journal of Medicinal Chemistry website:
4-[[2-(1-Methyl-2-pyrrolidinyl)ethyl]thio]- phenol Hydrochloride (SIB-1553A): A Novel Cognitive
Enhancer with Selectivity for Neuronal Nicotinic Acetylcholine Receptors
Jean-Michel Vernier,* Hassan El-Abdellaoui, Heather Holsenback, Nicholas D. P. Cosford, Leo Bleicher, Geoffrey Barker, Bruno Bontempi,
Laura Chavez-Noriega, Frederique Menzaghi, Tadimeti S. Rao, Richard Reid, Aida I. Sacaan, Carla Suto, Mark Washburn, G. Kenneth Lloyd,
and Ian A. McDonald
SIBIA Neurosciences Inc., 505 Coast Boulevard South, La Jolla, California 92037
Received January 21, 1999
Recent studies have revealed the existence of a family of presynaptic, neuronal acetylcholine ion channel receptors (nAChRs) in the brain which function to
modulate the release of neurotransmitters,1 such as acetylcholine (ACh), dopamine (DA), and other monoamines implicated in learning and memory
processes.2 There is convincing evidence to implicate a deficit of nAChRs in the symptomatology of Alzheimer's disease (AD). For example, studies have
demonstrated a substantial loss of nAChRs from cortical3 and hippocampal4 brain regions of AD patients and that this loss is dependent upon the particular
nAChR subtype composition.5 It is likely that efficacious nAChR agonists will stimulate the activity of the remaining intact nAChRs to compensate for this
loss. Furthermore, the neurotoxin -amyloid has been shown to attenuate nicotine-induced release of ACh and DA.6 Finally, the prototypical nAChR agonist
nicotine (1) has been shown to ameliorate some of the symptoms of AD7,8 and, in a number of animal models, to have neuroprotective effects.9 Thus,
subtype-selective nAChR agonists have the potential to treat a number of central nervous system (CNS) disorders such as Alzheimer's disease.
As a part of a program to identify compounds that selectively activate nAChRs which stimulate the release of certain neurotransmitters, we have reported that
SIB-1508Y (2) is being developed to treat the symptoms of Parkinson's disease which can be biochemically defined as a deficiency of dopamine.10 To develop
a useful therapeutic agent for Alzheimer's disease, we sought selective nAChR agonists which stimulate the release of acetylcholine from the hippocampus and
cortex, without concomitant activation of peripheral nAChRs |
