Full Text DA-97-003 DISCOVERY OF NOVEL PHARMACOTHERAPIES FOR COCAINE DEPENDENCE NIH GUIDE, Volume 25, Number 37, November 1, 1996 RFA: DA-97-003 P.T. 34 Keywords: Addiction Drugs/Drug Abuse Drug Design Chemical Synthesis National Institute on Drug Abuse Letter of Intent Receipt Date: February 13, 1997 Application Receipt Date: March 13, 1997 PURPOSE The purpose of this Request for Applications (RFA) is to encourage applications combining medicinal chemistry and preclinical pharmacology to design, synthesize and test compounds leading to the identification of candidates for advanced preclinical and clinical evaluation as potential pharmacotherapies for cocaine dependence. Pharmacological testing may be conducted using in vitro and/or non-human in vivo procedures. HEALTHY PEOPLE 2000 The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2000," PHS-led national activity for setting priority areas. This RFA, Discovery of Novel Pharmacotherapies for Cocaine Dependence, is related to the priority area of alcohol and other drugs. Potential applicants may obtain a copy of "Healthy People 2000" (Full Report: Stock No. 017-001-00474-0 or Summary Report: Stock No. 017-001-00473-1) through the Superintendent of Documents, Government Printing Office, Washington, DC 20402-9325 (telephone 202-512-1800). ELIGIBILITY REQUIREMENTS Applications may be submitted by domestic, for-profit and non-profit organizations, public and private, such as universities, colleges, hospitals, laboratories, units of State or local governments, and eligible agencies of the Federal Government. Racial/ethnic minority individuals, women, and persons with disabilities are encouraged to apply as principal investigators. Foreign institutions are not eligible for the First Independent Research Support and Transition (FIRST) (R29) award. MECHANISM OF SUPPORT This RFA will use the National Institutes of Health (NIH) research project grant (R01) and FIRST (R29) awards. Responsibility for the planning, direction, and execution of the proposed project will be solely that of the applicant. The total project period for an application submitted in response to this RFA may not exceed five years. The anticipated award date is September 30, 1997. Because of the nature and scope of the research proposed in response to this RFA may vary, it is anticipated that the size of an award will vary also. This RFA is a one-time solicitation. Future unsolicited competing continuation applications will compete with all investigator-initiated applications and be reviewed according to the customary peer review procedures. FUNDS AVAILABLE It is anticipated that approximately $1.5 million will be available to support projects submitted under this RFA. Because the nature and scope of the research proposed in response to this RFA may vary, the size of an award will vary also. It is anticipated that five to seven awards will be made. RESEARCH OBJECTIVES Background The discovery and development of pharmacotherapeutic agents for cocaine addiction is the predominant focus of the Medications Development Program at NIDA. In the area of cocaine dependence, there currently are no FDA-approved pharmacotherapies. Correspondingly, the clinical needs of cocaine dependent patients are broad; patients would likely benefit from pharmacotherapies acting to interrupt any stage of the cocaine dependence cycle. Following the medication discovery efforts supported by this RFA, it is anticipated that a few "promising" new compounds will advance through development and into clinical trials. NIDA is poised to facilitate this process; through existing NIDA contracts, follow-up behavioral studies may be conducted in rodents and/or monkeys, compound synthesis may be scaled up, and the gamut of safety assessments which might be required by the FDA may be conducted. Information on specific types of follow-up testing which are currently supported through NIDA contracts and agreements may be obtained by contacting the Programmatic Official indicated in the INQUIRIES section below. Areas of Research The primary intent of this RFA is to expand the NIDA Cocaine Treatment Discovery Program (CTDP) by increasing the flow of promising compounds via grant mechanisms. This is an effort to move these project areas in the direction of medicinal chemists working with biochemical and/or behavioral pharmacologists to design, synthesize and carry out sufficient preliminary in vitro and behavioral testing to allow for identification of "promising" candidates for advanced preclinical testing in the CTDP - or for advancement into toxicological testing as a clinical candidate - and to generate a portfolio of integrated research projects that involve single chemist/pharmacologist collaborations (primarily through the R01 mechanism), as well as program projects. Any approach to the design, synthesis, and preliminary testing of compounds with potential for yielding a pharmacotherapy for cocaine addiction in any of its stages (from acute blockage of cocaine effects to modulation of long term craving) is of high interest. Applications are expected to meet basic scientific standards of novelty and merit. Applications in the following areas are of particular interest: o Targeted design, synthesis and testing of potential medications which would act as full agonists, partial agonists, or pure antagonists (or prodrugs whose metabolism would result in such desired activity) at defined receptor targets (e.g., specific subtypes of dopamine receptors, CRF receptors, etc.) or which would act at other biochemical targets (e.g., biogenic amine transporters). The choice of each target must be supported by a strong rationale. Applicants are encouraged to consider the potential usefulness of compounds selective for D1 and/or D3 receptors as medications (e.g., references 1 and 2). o Design, synthesis and testing of potential medications which would produce one or more of the following effects in pharmacological studies: a relatively long duration of action; mild reinforcing and stimulant properties when compared to cocaine; and/or blockade of cocaine's effects in behavioral assays, including self-administration tests. o Molecular modeling as a tool to create small molecule mimetics to characterize the necessary orientation in space and electrostatic interactions of target receptors or transporters (with the choice of biochemical target supported by a strong rationale). o Development and screening of synthetic compound collections or libraries of chemical entities for potential cocaine pharmacotherapies (again, with the choice of biochemical target supported by a strong rationale). Investigators may wish to consider the utilization of robotic systems, as well as the screening of other compound ensembles, such as natural products and fermentation extracts. The application of other chemical diversity methods to the search for a specific activity of interest can also be considered. The above listing of specific research areas is not intended to be all-inclusive but is intended to give the applicant some direction regarding the types of efforts which NIDA may be interested in supporting. All applications should have a component to assess biological activity of synthesized compounds, in particular the generation of in vitro binding and functional activity data as a means of verifying a compound's primary mechanism of action. Behavioral assessment could include the use of animal models which may predict the efficacy of a medication (e.g., effects on cocaine stimulated locomotor activity, effects on cocaine drug discrimination in rodents, effects on cocaine self-administration behavior in rodents, effects in rodent place conditioning procedures, effects in rodent intracranial self-stimulation procedures, and especially effects in animal models of cocaine "craving" or relapse to cocaine use). References 1) Self et.al, Science (1996) 271(5255), p. 1586-9. 2) Caine and Koob, Behavioral Pharmacology (1995), 6, p. 333-347. LETTER OF INTENT Prospective applicants are asked to submit, by February 13, 1997, a letter of intent that includes a descriptive title of the proposed research, the name, address, and telephone number of the Principal Investigator, the identities of other key personnel and participating institutions, and the number and title of the RFA in response to which the application may be submitted. Although a letter of intent is not required, is not binding, and does not enter into the review of a subsequent application, the information that it contains allows NIDA staff to estimate the potential review workload and avoid conflict of interest in the review. The letter of intent is to be sent to: Director, Office of Extramural Program Review National Institute on Drug Abuse 5600 Fishers Lane Rockville, MD 20857 Telephone: (301) 443-2755 FAX: (301) 443-0538 APPLICATION PROCEDURES The research grant application form PHS 398 (rev. 5/95) is to be used in applying for these grants. Application kits are available at most institutional offices of sponsored research and may be obtained from the Grants Information Office, Office of Extramural Outreach and Information Resources, National Institutes of Health, 6701 Rockledge Drive, Bethesda, Maryland, 20892-7710, telephone 301/710-0267, email: asknih@odrockm1.od.nih.gov. The RFA label available in the PHS 398 application form must be affixed to the bottom of the face page of the application. Failure to use this label could result in delayed processing of the application such that it may not reach the review committee in time for review. In addition, the RFA title and number must be typed on line 2 of the face page of the application form and the YES box must be marked. Applications for the FIRST award (R29) must include at least three sealed letters of reference attached to the face page of the original application. FIRST award (R29) applications submitted without the required number of reference letters will be considered incomplete and will be returned without review. Submit a signed, typewritten original of the application, including the Checklist, and three signed photocopies, in one package to: DIVISION OF RESEARCH GRANTS NATIONAL INSTITUTES OF HEALTH 6701 ROCKLEDGE DRIVE, ROOM 1040 - MSC 7710 BETHESDA, MD 20892-771 BETHESDA, MD 20817 (for express/courier service) At the time of submission, two additional copies of the application must be sent to: Director, Office of Extramural Program Review National Institute on Drug Abuse Parklawn Building, Room 10-42 5600 Fishers Lane Rockville, MD 20857 Applications must be received by March 13, 1997. If an application is received after that date, it will be returned to the applicant without review. The Division of Research Grants (DRG) will not accept any application in response to this RFA that is essentially the same as one currently pending initial review, unless the applicant withdraws the pending application. The DRG will not accept any application that is essentially the same as one already reviewed. This does not preclude the submission of substantial revisions of applications already reviewed, but such applications must include an introduction addressing the previous critique. REVIEW CONSIDERATIONS Applications that are complete will be evaluated for scientific and technical merit by an appropriate peer review group convened in accordance with standard NIH peer review procedures. As part of the initial merit review, all applications will receive a written critique and undergo a process in which only those applications deemed to have the highest scientific merit, generally the top half of applications under review, will be discussed, assigned a priority score, and receive a second level review by the appropriate advisory council or board. Review Criteria o relevance to the goals and objectives of this RFA; o scientific, technical, or medical significance and originality of proposed research; o appropriateness and adequacy of the experimental approach and methodology proposed to carry out the research; o qualifications and research experience of the Principal Investigator and staff, particularly, but not exclusively, in the area of proposed research; o availability of the resources necessary to perform the research; o appropriateness of the proposed budget and duration in relation to the proposed research; and o adequacy of the plans to include both genders as appropriate for the scientific goals of the research (when the research involves human subjects). The initial review group will also examine the provisions for the protection of human and animals subjects, and the safety of the research environment. The review criteria and eligibility requirements for the First Independent Research Support and Transition (FIRST) Award are described in an NIH-wide announcement. The same criteria will be applied in reviewing FIRST award applications received in response to this RFA. However, these applications must also be relevant to the goals and objectives of this RFA. This announcement can be generally obtained from the office of sponsored research at most academic institutions or by calling Dr. Biswas at the address listed under INQUIRIES. AWARD CRITERIA Applications recommended for further consideration by an appropriate Advisory Council will be considered for funding based on the following factors: overall scientific and technical merit of the proposal as determined by peer review; significance and originality of the proposed research; appropriateness of budget estimates; program priorities; and availability of funds. INQUIRIES Inquiries concerning this RFA are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Direct inquiries regarding programmatic issues to: Jamie Biswas, Ph.D. Medications Development Division National Institute on Drug Abuse 5600 Fishers Lane, Room 11A-55 Rockville, MD 20857 Telephone: (301) 443-5280 FAX: (301) 443-2599 Email: jb168r@nih.gov Direct inquiries regarding fiscal matters to: Gary Fleming, J.D., M.A. Grants Management Branch National Institute on Drug Abuse 5600 Fishers Lane, Room 8A-54 Rockville, MD 20857 Telephone: (301) 443-6710 FAX: (301) 594-6847 Email: gf6s@nih.gov AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.279. Awards are made under authorization of Section 301 of the Public Health Service Act (42 USC 241) and administered under PHS policies and Federal Regulations at Title 42 CFR 52 "Grants for Research Projects," Title 45 CFR Part 74 & 92, "Administration of Grants" and 45 CFR Part 46, "Protection of Human Subjects." This program is not subject to the inter-governmental review requirements of Executive Order 12372 or Health Systems Agency review. The PHS strongly encourages all grant recipients to provide a smoke-free workplace and promote the non-use of all tobacco products. In addition, Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking in certain facilities (or in some cases, any portion of a facility) in which regular or routine education, library, day care, health care or early child development services are provided to children. This is consistent with the PHS mission to protect and advance the physical and mental health of the American people. .
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