Selective α7 Nicotinic Acetylcholine Receptor Ligands

Abstract

Neuronal nicotinic acetylcholine receptors (nAChRs) are ligand gated ion channels of broad distribution and structural heterogeneity. Their functional diversity demonstrated involvement in a variety of neuronal processes (e.g., sensory gating and cognitive function) and generated great interest in them as targets for therapeutic intervention in a number of neuropathological conditions and diseases. In order to control distinct nicotinic functions pharmacologically, it is important to design ligands that selectively interact with distinct receptor subtypes in such a way as to maximize the therapeutic effect and minimize the adverse effects. The alpha7 nAChR, a CNS subtype, has been the most intensively studied nAChR in recent years. Selective alpha7 nAChR agonists have been developed as potential candidates for the treatment of schizophrenia, cognitive disorders (including Alzheimer's disease), and inflammation. Despite early concerns that the rapid desensitization property of the alpha7 nAChR would limit their therapeutic potential, several have already been advanced to clinical trials (e.g., PH-399733, Pfizer; MEM 3454, Memory Pharmaceuticals/Roche). Further development of allosteric modulators and pharmaceutically relevant antagonists might expand the therapeutic potential of compounds that target alpha7 nAChRs. In this review we briefly describe the structure and function of the alpha7 nAChR and its in vitro and in vivo pharmacology, discuss the clinical relevance of these efforts, and review the current progress in alpha7 ligand development.

FTIR microspectroscopic analysis of the effects of certain drugs on oxidative stress and brain protein structure

“…The treatments of the different rat groups were as follows: (A) saline (NaCl 0.9%) control solution; (B) nicotine ( [2] nicotine hydrogen tartrate salt; Sigma Chem, St. Louis, MO), at a daily dose of 1 mg/kg-equivalent to 0.35 mg of (2)-nicotine free base/kg/ day; (C) amphetamine (D(1)-amphetamine sulfate salt; Uquifa Lab, Barcelona, Spain), at a daily dose of 4 mg/kg-equivalent to 3.92 mg of D(1)-amphetamine free base/kg/day; and (D) nicotine and D(1)-amphetamine (both drugs administered simultaneously at the above doses). The nicotine dose administered was the same as that used in previous work showing it to be responsible for dehydrogenase activation and NGF induction, but not the induction of apoptosis.…”

“…1,2 Nicotine and its nontoxic derivatives have been reported to improve cognitive ability by acting directly or indirectly on the cortical neurons. [3][4][5][6] However, many of the neuronal changes that nicotine induces are poorly understood.…”

A Randomized Trial to Assess the Efficacy and Safety of ABT-126, a Selective α7 Nicotinic Acetylcholine Receptor Agonist, in the Treatment of Cognitive Impairment in Schizophrenia

“…Alpha-7 (a7) neuronal nicotinic receptors play a key role in cognitive function (4)(5)(6). a7 Neuronal nicotinic receptors are localized on presynaptic and postsynaptic elements in the hippocampus and cerebral cortex, regions critical to the synaptic plasticity underlying learning and memory (6,7).…”

The α7 nicotinic acetylcholine receptor on fibroblast‐like synoviocytes and in synovial tissue from rheumatoid arthritis patients: A possible role for a key neurotransmitter in synovial inflammation

“…After 24-hour stimulation the antiinflammatory effects of both agonists were diminished in vitro (data not shown). It is known that the ␣7nAChR displays fast (millisecond) onset of desensitization upon agonist application (46), so this phenomenon could be caused by desensitization and loss of biologic response of the receptor due to sustained agonist stimulation.…”