The inventors have isolated and characterized an alkaloid, phantasmidine, from the skin of the Ecuadoran poison frog E. anthonyi. Phantasmidine is selective for beta4-containing receptor subtypes, unlike many nicotinic receptor agonists currently in development, which target beta2-containing receptor subtypes. This selectivity makes phantasmidine a unique pharmacological probe, as well as a promising lead compound for the development of selective therapeutics targeting beta4-containing receptor subtypes, which appear to play any important role in nicotine addiction and other substance dependencies.
Nicotinic acetylcholine receptors (nAChRs) are broadly distributed in both the peripheral and central nervous systems; activation of brain nAChRs results in enhanced release of various key neurotransmitters. Dysfunction of these receptors is associated with a variety of neurological diseases, including nicotine addiction. Nicotinic agonists, which enhance action at nicotinic acetylcholine receptors, have been shown to possess potential clinical utility in many of these diseases, although development is hindered by the existence of a large number of nAChR subtypes with highly variable properties.
Alkaloids, such as epibatidine found in skin from the frog species E. tricolor, have been shown to activate nicotinic acetylcholine receptors. However, while epibatidine has been shown to be a powerful analgesic, it is also extremely toxic, so research has focused on the identification and development of less toxic analogs.
- Development of therapies for the treatment of addiction, including nicotine and alcohol addictions.
- Development of therapies for neurological diseases such as Alzheimer’s disease, attention deficit hyperactivity disorder (ADHD), and schizophrenia.
- Development of selective pharmacological probes for bioimaging, binding assays, and functional assays of nicotinic receptors.