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a7 agonist

Nicotinic Agonists and Antagonists. Fig. 8. Structures of nAChR ligands discussed for pain.

reported to have analgesic activity, has an affinity for a7 nAChRs.

Since neither nicotine nor epibatidine can be used clinically owing to safety concerns at analgesic doses, synthetic nAChR agonists are being pursued as analgesics and most research has focused on selective a4b2 agonists. The a4b2 nAChR agonist ABT-594 (Fig. 8) is structurally related to epibatidine with similar analgesic potency, but its development was not pursued owing to limited tolera-bility. Similarly, the development of two other selective a4b2 nAChR agonists, TC-2696 (Fig. 8) and TC-6499 (structure not disclosed), which had shown analgesic efficacy in preclinical pain models, was halted because of lack of efficacy and an insufficient therapeutic index. More promising is a second-generation a4b2 full agonist, ABT-894 (structure not disclosed), which is currently under development for neuropathic pain.

While the clinical evidence for analgesic efficacy of selective a4b2 nAChR ligands is still limited, the possibility remains that the activity at other nAChR subtypes contributes to analgesic efficacy.


Our increased understanding of nAChR pharmacology and how agonists, partial agonists, and antagonists modulate the function of these receptors has led to the discovery of a large number of selective ligands that are being used either as tools for exploring the role(s) of nAChR subtypes or are in the preclinical or clinical stage of development as potential new pharmacotherapies. Several compounds represent promising new treatments for disorders in which nAChRs are thought to participate. However, the fact that to date very few nAChR ligands have been approved for clinical use illustrates the tremendous challenge of developing selective nicotinic compounds as novel medications without major side effects. The high degree of homology between the different receptor subtypes calls for a better knowledge of their function and distribution throughout the body and for the finding of subtype-selective compounds. In addition, high selectivity is essential for an acceptable side-effect profile to avoid interactions with peripheral muscle and ganglionic nAChR subtypes associated with cardiovascular, gastrointestinal, and respiratory adverse events. Clearly, progress in the development of novel drugs that target nAChR subtypes is dependent on the design and discovery of highly selective ligands with sufficient potency and adequate pharmacokinetic properties to have efficacy at doses at which selectivity is maintained.

Acknowledgment and Disclosure

HR and RSH are employees of Pfizer, Inc. DB was supported by the Swiss National Science Foundation. Editorial support was provided by Alexandra Bruce, PhD, of UBC Scientific Solutions, and was funded by Pfizer, Inc.


► Acetylcholine

► Adverse Effect

Alcohol Abuse and Dependence

Alzheimer's Disease

► Antagonist

► Anti-Parkinson Drugs


Attention Deficit Hyperactivity Disorder

► Cognitive Enhancers

► Cognitive Enhancers: Novel Approaches

► Electroencephalography

► Endophenotype

Nicotine Dependence and Its Treatment

► Nicotinic Receptor

► Parkinson's Disease

► Partial Agonist

► Rodent Tests of Cognition



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