According to the National Institute of Mental Health (NIMH), an estimated 26.2% of Americans ages 18 and above suffer from a diagnosable mental disorder in a given year. This percentage translates to about 60 million people per year using 2004 census figures. The long term goal of this proposal is to develop new agents that have improved therapeutic profiles over the current antipsychotics and antidepressants in use. Atypical Antipsychotic Agents (AAAs) or Second Generation Antipsychotics (SGAs), typified by clozapine and olanzapine, have replaced typical antipsychotic agents (TAAs) as the drugs of choice for the treatment of schizophrenia due to their superior side effect profiles. However, AAAs have now been found to produce a new set of adverse events including weight gain, obesity, type II diabetes, seizures, hypotension, hyperlipidemia and cardiovascular disease (CVD). Several of these new side effects have been linked to specific receptors in the CNS or the periphery. Thus, the goal of this research proposal is three-fold: to move a new lead identified in our laboratories towards the clinic by validating its in vivo activities, to optimize another new lead (SYA038) with the potential to overcome the side effects associated with the current AAAs and to optimize a third new lead compound (SYA031) with the potential to overcome the initial delay associated with serotonin reuptake inhibitors (SSRIs) in the treatment of depression and to improve their therapeutic efficacy. The following specific aims are proposed to achieve the objectives of the proposal: i) To validate the in vivo efficacy of SYA 013 in animal models of schizophrenia and to conduct bioavailability and pharmacokinetic analyses, ii) To conduct SAR studies on a new lead compound, SYA038, discovered during the previous MBRS cycle in order to optimize its affinity to both D2 and 5HT1A receptors but exclude high affinity at receptors linked to the adverse events, iii) To expand our exclusive focus on antipsychotic agents to a focus on novel antidepressants using a newly identified agent SYA031 with specific binding affinity for the serotonin transporter (SERT) and 5HT1A as a lead. Drugs with a combined capacity to inhibit SERT and 5HT1A may represent a novel class of drugs for treating depression. Achieving the specific aims will also provide preliminary data and improve our research environment such that we would become more competitive to apply for non-SCORE R-series grants from the NIH NIMH by the end of the grant period.

Public Health Relevance

According to the National Institute of Mental Health (NIMH), an estimated 26.2% of Americans ages 18 and above suffer from a diagnosable mental disorder in a given year. This percentage translates to about 60 million people per year using 2004 census figures. The long term goal of this proposal is to develop new agents that have improved therapeutic profiles over the current antipsychotics and antidepressants in use. Providing new drugs for Schizophrenia and depression will elevate adverse side-effects associated with the current drugs and reduce health care cost associated with this debilitating illness. Achieving the specific aims will also provide preliminary data and improve our research environment such that we would become more competitive to apply for non-SCORE R-series grants from the NIH NIMH by the end of the grant period.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Enhancement Award (SC1)
Project #
5SC1GM088451-03
Application #
8106145
Study Section
Special Emphasis Panel (ZGM1-MBRS-X (CH))
Program Officer
Fabian, Miles
Project Start
2009-08-15
Project End
2013-06-30
Budget Start
2011-07-01
Budget End
2012-06-30
Support Year
3
Fiscal Year
2011
Total Cost
$251,213
Indirect Cost
Name
Florida Agricultural and Mechanical University
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
623751831
City
Tallahassee
State
FL
Country
United States
Zip Code
32307
Sampson, Dinithia; Zhu, Xue Y; Eyunni, Suresh V K et al. (2014) Identification of a new selective dopamine D4 receptor ligand. Bioorg Med Chem 22:3105-14
Sampson, Dinithia; Bricker, Barbara; Zhu, Xue Y et al. (2014) Further evaluation of the tropane analogs of haloperidol. Bioorg Med Chem Lett 24:4294-7
Bricker, Barbara; Sampson, Dinithia; Ablordeppey, Seth Y (2014) Evaluation of the potential of antipsychotic agents to induce catalepsy in rats: assessment of a new, commercially available, semi-automated instrument. Pharmacol Biochem Behav 120:109-16
Bricker, Barbara; Jackson, Tanise; Boateng, Bernard et al. (2012) Evaluation of the behavioral and pharmacokinetic profile of SYA013, a homopiperazine analog of haloperidol in rats. Pharmacol Biochem Behav 102:294-301
Zhu, Xue Y; Etukala, Jagan R; Eyunni, Suresh V K et al. (2012) Benzothiazoles as probes for the 5HT1A receptor and the serotonin transporter (SERT): a search for new dual-acting agents as potential antidepressants. Eur J Med Chem 53:124-32
Peprah, Kwakye; Zhu, Xue Y; Eyunni, Suresh V K et al. (2012) Multi-receptor drug design: Haloperidol as a scaffold for the design and synthesis of atypical antipsychotic agents. Bioorg Med Chem 20:1291-7
Peprah, Kwakye; Zhu, Xue Y; Eyunni, Suresh V K et al. (2012) Structure-activity relationship studies of SYA 013, a homopiperazine analog of haloperidol. Bioorg Med Chem 20:1671-8
Sikazwe, Donald M N; Nkansah, Nancy T; Altundas, Ramazan et al. (2009) Synthesis and evaluation of ligands for D2-like receptors: the role of common pharmacophoric groups. Bioorg Med Chem 17:1716-23