Alpha7 neuronal nicotinic receptors as a drug target in schizophrenia.

SRI International , 333 Ravenswood Avenue, Menlo Park, CA , USA.
Expert Opinion on Therapeutic Targets (Impact Factor: 4.9). 12/2012; DOI: 10.1517/14728222.2013.736498
Source: PubMed

ABSTRACT Introduction: Schizophrenia is a profoundly debilitating disease that represents not only an individual, but a societal problem. Once characterized solely by the hyperactivity of the dopaminergic system, therapies directed to dampen dopaminergic neurotransmission were developed. However, these drugs do not address the significant impairments in cognition and the negative symptoms of the disease, and it is now apparent that disequilibrium of many neurotransmitter systems is involved. Despite enormous efforts, minimal progress has been made toward the development of safer, more effective therapies to date. Areas covered: The high preponderance of smoking in schizophrenics suggests that nicotine may provide symptomatic improvement, which has led to investigation for selective molecules targeted to individual nicotinic receptor (nAChR) subtypes. Of special interest is activation of the homomeric α7nAChR, which is widely distributed in the brain and has been implicated in the pathophysiology of schizophrenia through numerous approaches. Expert opinion: Preclinical and clinical data suggest that neuronal α7nAChRs play an important role in cognitive functions. Moreover, some, but not all, early clinical trials conducted with α7nAChR agonists show cognitive benefits in schizophrenics. These encouraging results suggest that development of compounds targeting α7nAChRs will represent a valuable tool to mitigate symptoms associated with schizophrenia, and open new strategies for better pharmacological treatment of these patients.

1 Follower
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Alpha7 nicotinic acetylcholine receptors (nAChRs) have implications in the regulation of cognitive processes such as memory and attention and have been identified as a promising therapeutic target for the treatment of the cognitive deficits associated with schizophrenia and Alzheimer's disease (AD). Structure affinity relationship studies of the previously described α7 agonist SEN12333 (8), have resulted in the identification of compound 45, a potent and selective agonist of the α7 nAChR with enhanced affinity and improved physicochemical properties over the parent compound (SEN12333, 8). Copyright © 2015 Elsevier Masson SAS. All rights reserved.
    European Journal of Medicinal Chemistry 03/2015; 95. DOI:10.1016/j.ejmech.2015.03.025 · 3.43 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Cys-loop receptors are neurotransmitter-activated ion channels involved in synaptic and extrasynaptic transmission in the brain and are also present in non-neuronal cells. As GABAA and nicotinic receptors (nAChR) belong to this family, we explored by macroscopic and single-channel recordings if the inhibitory neurotransmitter GABA has the ability to activate excitatory nAChRs. GABA differentially activates nAChR subtypes. It activates muscle nAChRs, with maximal peak currents of about 10 % of those elicited by ACh and 15-fold higher EC50 with respect to ACh. At the single-channel level, the weak agonism is revealed by the requirement of 20-fold higher concentration of GABA for detectable channel openings, a major population of brief openings, and absence of clusters of openings when compared to ACh. Mutations at key residues of the principal binding-site face of muscle nAChRs (αY190 and αG153) affect GABA-activation similarly as ACh-activation whereas a mutation at the complementary face (ϵG57) shows a selective effect for GABA. Studies with subunit-lacking receptors show that GABA can activate muscle nAChRs through the α/δ interface. Interestingly, single-channel activity elicited by GABA is similar to that elicited by ACh in gain-of-function nAChR mutants associated to congenital myasthenic syndromes, which could be important in the progression of the disorders due to steady exposure to serum GABA. In contrast, GABA cannot elicit single-channel or macroscopic currents of α7 or the chimeric α7-5HT3A receptor, a feature important for preserving an adequate excitatory/inhibitory balance in the brain as well as for avoiding activation of non-neuronal receptors by serum GABA. The American Society for Pharmacology and Experimental Therapeutics.
    Molecular pharmacology 12/2014; 87(3). DOI:10.1124/mol.114.095539 · 4.12 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Positive allosteric modulators (PAMs) for the α7 nicotinic receptor hold promise for the treatment of sensory inhibition deficits observed in schizophrenia patients. Studies of these compounds in the DBA/2 mouse, which models the schizophrenia-related deficit in sensory inhibition, have shown PAMs to be effective in improving the deficit. However, the first published clinical trial of a PAM for both sensory inhibition deficits and related cognitive difficulties failed, casting a shadow on this therapeutic approach. The present study used both DBA/2 mice, and C3H Chrna7 heterozygote mice to assess the ability of the α7 PAM, PNU-120596, to improve sensory inhibition. Both of these strains of mice have reduced hippocampal α7 nicotinic receptor numbers and deficient sensory inhibition similar to schizophrenia patients. Low doses of PNU-120596 (1 or 3.33mg/kg) were effective in the DBA/2 mouse but not the C3H Chrna7 heterozygote mouse. Moderate doses of the selective α7 nicotinic receptor agonist, choline chloride (10 or 33mg/kg), were also ineffective in improving sensory inhibition in the C3H Chrna7 heterozygote mouse. However, combining the lowest doses of both PNU-120596 and choline chloride in this mouse model did improve sensory inhibition. We propose here that the difference in efficacy of PNU-120596 between the 2 mouse strains is driven by differences in hippocampal α7 nicotinic receptor numbers, such that C3H Chrna7 heterozygote mice require additional direct stimulation of the α7 receptors. These data may have implications for further clinical testing of putative α7 nicotinic receptor PAMs. Copyright © 2015. Published by Elsevier B.V.


Available from
Jun 6, 2014