Aim 1 is to perform a Phase 1 safety and pharmacokinetic study of UCI-40083 in healthy persons. The study will test an escalating range of single oral doses to determine if adequate plasma levels are reached and what side effects are encountered. Specific EEG and neurocognitive monitoring will be performed, because the primary target is brain receptors. The study will be performed first in non-smokers and then extended to persons who smoke to assess possible interaction with nicotine.
Aim 2 is to perform a Phase lb safety, pharmacokinetic, and preliminary efficacy study of UCI-4083 in persons with schizophrenia. This single oral dose double-blind placebo-controlled, study will be modeled on the results ofthe Aim 1 study, with a dose range identified by Aim 1 as safe and adequate to achieve putatively therapeutic levels. In previous work with the a7-nicotinic receptor selective partial agonist 3-2,4 dimethxoybenzylidene anabaseine (DMXB-A), we performed a similar Phase lb single dose study. In addition to the primary outcome of improvement in neurocognition, we used the inhibition of auditory cerebral evoked response to repeated sounds, measured by the P50 wave ofthe auditory evoked potential, to assess the neurobiological response to the drug. Animal model studies with UCI-40083 have shown positive effects on this same inhibitory function (Project 3). Thus, this project is the human translation equivalent of Project's 3's animal modeling ofthe effects of UCI-40083.
Aim 3 is to perform an initial Phase 2 proof-of-principle clinical study of UCI-40083 in schizophrenia. Persons with schizophrenia will receive UCI-4083 for 4 weeks in an outpatient, placebocontrolled double-blind study. The primary outcome will be performance on the NIMH MATRICS Consensus Cognitive Battery. To assess neurobiological effects, functional MRl studies during eye tracking and the default mode will be added to the P50 auditory evoked potentials recorded in Aim 2. Pharmacogenomic effects of single nucleotide polymorphisms in the CHRNA7 promoter were observed with DMXB-A and we will therefore investigate whether similar effects are seen for UCI-40083.

Public Health Relevance

Persistent neurocognitive deficits, psychosocial disability, and negative symptoms are evidence that current neuroleptic therapies, which primarily inhibit dopamine D2 receptors, are insufficient treatment for schizophrenia. Alpha7-nicotinic receptor activation is a potential additional target for drug therapy. UCI- 40083 is the first of a new class of drug that can improve alpha7-nicotinic receptor function.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Project--Cooperative Agreements (U01)
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Special Emphasis Panel (ZMH1-ERB-C (04))
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University of Colorado Denver
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