Neuroprotective Potential Of Neuronal Nicotinic Acetylcholine Receptor Ligands
In a presentation at Duke University on November 4, scientists from SIBIA Neurosciences, Inc. (La Jolla, CA) reported on preclinical studies of SIB-1508Y. This agent, one of Sibia's neuronal nicotinic acetylcholine receptor (nAChR) agonists, which is currently in Phase 2 clinical trials, has shown the ability to protect neurons from degenerative changes in a rodent model of Parkinson's disease.
Previous studies in rat and primate models of Parkinson's disease suggested that SIB-1508Y could offer new advantages over existing Parkinson's disease therapies because of its ability to improve both cognitive and motor deficits. It is now recognized that cognitive impairment is a serious and frequent symptom in many Parkinson's patients, but no available product addresses this aspect of the disease. The animal data on neuroprotection suggests the potential for this compound for treating not only the cognitive and motor symptoms of Parkinson's, but to retard the degeneration of neurons, a hallmark of the disease process.
Human Parkinson's disease is characterized by loss of the neurotransmitter dopamine in the nigrostriatal pathway, resulting in marked impairment of movement and often accompanied by deficits in affect and cognition. In the studies reported by Tadimeti Rao, Associate Research Director at SIBIA, SIB-1508Y offered protection against the decrease in dopamine levels in the striatum and substantia nigra in rat models of Parkinson's disease following injection of a neurotoxin, 6-OHDA, into the rat striatum. This type of lesion damages dopamine neuron terminals in the striatum and leads to a progressive degeneration of the dopamine cell bodies in the substantia nigra.
The best protection was seen when SIB-1508Y was given before the 6-OHDA injection and followed by continued administration over a period of four weeks. In this paradigm, SIB-1508Y was able to completely protect against toxin-induced loss of dopamine in the substantia nigra and protect up to 75% of the dopamine loss in the striatum. In addition, the repeated administration of SIB-1508Y increased levels of choline acetyltransferase, an enzyme involved in the synthesis of acetylcholine, an important neurotransmitter for cognition.
Sibia's nAChR Program
In the late 1980s, SIBIA began exploring nAChR subtypes as targets for drug discovery because of the growing awareness of the importance of the nAChR system and its endogenous neurotransmitter, acetylcholine, in excitatory processes. By this point a number of distinct nAChR subtypes and the complex pharmacology of the exogenous ligand nicotine had been established. The complexity of nicotine's activity was believed to be due to its non-selective nature (acting at all nAChRs), and SIBIA sought to separate the potential therapeutic benefits of nicotinic compounds from less desirable effects with receptor subtype-selective compounds.
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Until recently, the pharmaceutical industry has not focused on nAChRs as important drug targets. Mapping and pharmacological studies have revealed that nAChR subtypes are widely but discretely distributed in the brain and appear to be associated with specific neuronal structures and functions.
Strong evidence suggests that nAChRs are important in a number of nervous system disorders. In particular, deficits of nAChRs have been demonstrated in Parkinson's and Alzheimer's patients. Studies at Sibia indicate that nAChRs are involved in modulating the release of dopamine, acetylcholine and other important neurotransmitters in different brain regions. The company hopes to develop subtype-selective nAChR drugs, such as SIB-1508Y and SIB-1553A, to ameliorate the disease symptoms that result from reduced concentrations of dopamine and acetylcholine in Parkinson's and Alzheimer's patients, respectively. Sibia is banking on the possibility that nAChR compounds with different subtype selectivities may be useful for the treatment of other nervous system disorders such as schizophrenia, ADHD, depression and chronic pain as well as nervous system-related addictive behaviors, such as eating disorders and smoking addiction.
SIB-1508Y has been tested in a number of animal models, and demonstrated activity in rodent and primate models of Parkinson's disease, in rodent models of depression and in primate models of cognitive function. Pre-clinical data suggests that SIB-1508Y may be useful both as a stand-alone therapeutic agent and as an adjunctive therapy with L-dopa. In September 1997, Sibia completed Phase I clinical trials of SIB-1508Y and commenced Phase II clinical trials of SIB-1508Y in Parkinson's disease patients in early 1998. In May 1998, the Company modified the protocol for Phase II, which involved a reduction in dose levels and a change in dosing schedule for new patients entering the trial. The first Phase II trial is a multi-site, placebo-controlled study with motor and cognitive endpoints, should be completed in 1999, assuming satisfactory patient recruitment rates.
For more information: Sharon Bowes, Sibia, Inc., 505 Coast Boulevard South, Suite 300, La Jolla CA 92037-4641. Tel: 619-452-5892. Fax: 619-459-1609.