Full Text DA-97-003
NIH GUIDE, Volume 25, Number 37, November 1, 1996
RFA:  DA-97-003
P.T. 34

  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
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.
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).
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.
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.
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.
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
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
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).
1) Self et.al, Science (1996) 271(5255), p. 1586-9.
2) Caine and Koob, Behavioral Pharmacology (1995), 6, p. 333-347.
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
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:
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:
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.
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
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 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
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
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

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