DEPARTMENT OF HEALTH AND HUMAN SERVICES
National Institutes Of Health

National Institute of Environmental Health Sciences:
Opportunity for a Cooperative Research and Development Agreement
(CRADA) for the Application of Highly Potent and Ultraselective ë
Opioidmimetic Peptide Antagonists for Biochemical,
Pharmacological, Clinical and Therapeutic Studies

AGENCY: National Institute of Environmental Health Sciences,
National Institutes of Health, PHS, DHHS

ACTION: Notice

SUMMARY: The National Institutes of Health (NIH) seeks an
agreement with a company(s) which can pursue commercial
development of highly selective ë opioid dipeptide antagonists
(U.S. Patent Application Serial No. 08/347,531). The National
Institute of Environmental Health Sciences has also determined
that the developed technology can be utilized in several
scientific areas, including development of a radiochemically
labelled ligand, production of gram quantities of the dipeptide,
application in the treatment of many clinical syndromes with
therapeutic application to numerous health problems. A CRADA for
the application of these compounds will be granted to the
awardee(s).

ADDRESSES: Proposals and questions about this opportunity may be
addressed to Dr. Lawrence H. Lazarus, NIEHS, Mail Drop C3-04,
P.O. Box 12233, Research Triangle Park, NC 27709; Telephone
919/541-3238; Fax 919/541-0626; Email Lazarus@niehs.nih.gov

Requests to view the patent application and questions related to
licensing this technology should be addressed to Leopold J.
Luberecki, Jr., J.D., Office of Technology Transfer, National
Institutes of Health, 6011 Executive Boulevard, Suite 325,
Rockville, MD 20852-3804 (Telephone: 301/496-7735 ext. 223; Fax:
301/402-0220).

Respondees interested in submitting a CRADA proposal should be
aware that it may be necessary to secure a license to the above
patent rights in order to commercialize products arising from a
CRADA agreement.

DATE: Capability statements must be received by NIH on or before
May 21, 1996.

SUPPLEMENTARY INFORMATION:
The National Institute of Environmental Health Sciences has
determined the specific chemical structure, high potency and
selectivity of a series of unique opioid di- and tripeptide
antagonists. The most active dipeptide exhibited an affinity for
the ë opioid receptor of 0.022 nM and a ë selectivity of 150,000
(relative to the þ receptor); affinity toward þ receptors was
negligible (> 20 þM). The tripeptide had ë selectivity of 20,000
and was similarly without effect on þ receptors (> 50 þM).
Pharmacological functional bioassays in vitro indicated
antagonistic activity at ë receptors without activity toward þ
receptors (> 10 þM), which makes these compounds more utilitarian
than the commonly employed ë antagonist naltrindole. Similarly,
in vivo data in mice confirmed the antagonistic behavior of these
peptides. Furthermore, the molecular model of the low energy
conformer indicated a unique solution topography of a universal
antagonist.

The commercial advantage of these substances is manifold:
1. The preparation of radiolabelled ligands for the
biochemical characterization of the ë opioid receptor,
localization of this receptor in animal tissues by various
immunohistochemical methods, and body distribution/
compartmentalization kinetics, such as in determining the extent
of transit across the blood-brain barrier. Current radioactive
opioid ligands generally have lower affinities and are
considerably less selective by orders of magnitude than our
opioid dipeptide.
2. The preparation of large quantities of highly pure
peptide for pharmacological and physiological studies in the
laboratory, and their availability for animal and clinical
trials, and eventually for therapeutic applications in medical
orientated facilities. For example, the potential for treatment
of alcohol dependency and narcotic addiction, obesity, and
suppression of the immune response in organ transplants, in
addition to other numerous clinical situations. These proposed
studies would eventually necessitate multigram quantities of the
dipeptide in spite of its high affinity and selectivity.
3. Production of monoclonal antibodies to these peptides
would provide science with high affinity substances that could be
effectively used in both the laboratory and clinical settings.

The CRADA awardees will have an option to negotiate for an
exclusive license to market and commercialize any new technology
developed within the scope of the research plan for the
ultraselective ë opioid dipeptide antagonists. This CRADA may be
directed toward the preparation of radioligands, synthesis of
gram quantities of peptide, its application in animal model
studies, as well as in clinical and therapeutic situations, and
in the formation of monoclonal antibodies.

Roles of NIEHS
1. Provide design and specifications of synthesizing the
opioid dipeptide and assist in beta testing both the labeled and
unlabeled ligands, and monoclonal antibodies.
2. Work cooperatively with the company(s) to determine the
market potential for these opioidmimetic peptides.

Roles of the CRADA Partner
1. Provide expertise in application and commercial-oriented
production of large quantities of opioid peptides.
2. Provide knowledge on the formation, purification, and
stabilization of radioactive substances.
3. Provide the expertise for the production of high
affinity, high specific monoclonal antibodies.
4. Develop a plan for the production, testing and
commercialization of the dipeptide, radiolabelled compounds and
monoclonal antibodies.

Selection criteria for choosing the CRADA partner(s) will
include, but will not be limited to the following:
1. Experience in peptide synthesis.
2. Capability to produce stable radiolabeled peptides with
high specific activity.
3. Ability to develop, implement and manage the product
commercialization so as to ensure the dissemination of the
substances to research or health care services.
4. Capacity to test labeled peptides and monoclonal
antibodies.

_____________________
Published in the Federal Register on Friday, March 22, 1996, pp 11852-11853
[61 FR 11852]