Alzheimer’s disease (AD) is an irreversible neurodegenerative disease of old age. The main pathological features of AD, Aβ-amyloid plaques,intraneuronal neurofibrillary tangles (NFT) and neurodegeneration of cholinergic neurons are the primary characteristics. It is believed that the pathological changes in cholinergic neurotransmission are responsible for the early clinical signs of AD such as the loss of short term memory, orientation, judgment and cognition.
Therapeutic Approaches to Cholinergic Deficits and Cognitive Decline:
Compounds that improve cholinergic functioning, e.g. acetylcholinesterase inhibitors (AChE-I), ameliorate the cognitive deficits in patients suffering from AD. However, AChE-I only provide suboptimal palliative treatment. Currently, the most widely used AChE-I is Aricept. The positive impact on other behavioral impairments that represent a major factor increasing the care burden is rather low. Therefore, more efficacious drugs are urgently needed to improve the treatment of AD patients in order to reduce the high and growing direct (loss of patient health) and indirect (caregiver) costs.
Nicotine enhances cognitive functions, such as learning, memory, and retention through activation of brain nicotinic acetylcholine receptors (nAChRs). The most common nicotinic receptors found in the brain are the low affinity a 7-nAChR and the high affinity a 4b2-nAChR. a 7– and a 4b2-nAChR agonists possess cognitive-enhancing properties. The ß2-subunit but not the a7-nAChRs mediates the addictive properties and some of the side-effects of nicotine. a 7-nAChRs are located in brain areas important for cognition. Selective activation of a 7-nAChRs may thus alleviate the cholinergic deficit present in AD without the undesirable side-effects caused by overactivation of other nAChRs or muscarinic acetylcholine receptors involved in addiction, cardiovascular or gastrointestinal functions. These side effects limit the doses of AChE-I tolerated and thus the level of cholinergic activation mediated by these compounds. Similarly nicotinic agonists without selective actions on a 7-nAChRs have been associated with dose limiting side effects. Various studies have reported modest reductions or no changes of a 7-nAChR levels in AD brain. a 7-nAChR agonists should therefore still active in the later stages of the disease, when cholinergic neurons have died and AChE-I loose their therapeutic efficacy. Like AChE-I such as donepezil (Aricept), selective a 7-nAChR agonists are expected to improve both acquisition and retention processes. In addition, a 7-nAChR agonists may have beneficial effects on other behavioral parameters, such as the psychiatric status of AD and other patients with hallucinations, anxiety or disturbed circadian rhythms.
EnVivo’s Cholinergic Nicotinic Agonist Program
The program was in-licensed from Bayer Healthcare and included an extensive and exclusive patent estate surrounding the compounds’ composition-of-matter.
EnVivo is developing a robust program of selective, orally active alpha-7 nicotinic acetylcholine receptor agonists for treatment of the cognitive decline in Alzheimer’s disease. Optimization of these compounds is based not only on binding to the alpha-7 receptor but also on functional channel activity. The program is expected to enter the clinic for Alzehimer’s disease in the second half of 2006. It is anticipated that these compounds may also have efficacy in other conditions with cognitive deficits such as schizophrenia.