The recent advent of combinatorial libraries composed of tens to hundreds of millions of peptides and nonpeptides offers an unparalleled opportunity to identify novel, highly receptor-specific ligands for the known opioid receptor subtypes. We propose to use this novel approach for the identification of highly selective ligands, both agonist and antagonist, for the three opioid receptors mu, delta, and kappa. These three opioid receptors all mediate analgesia; however, the type of pain inhibited, as well as their secondary functions, have been shown to differ. Differences in receptor functions encourage the search for drugs that produce analgesia without the known deleterious side effects of morphine and other opiate analgesic agents. Opioid agonists and antagonists with high selectivity for each of the different opioid receptors (mu, delta, kappa) and their subtypes are required for the study of opioid pharmacology, and can also serve as potential pharmaceutical agents or leads for drug development. In spite of improvements in specificity and activity of naturally-occurring opioids, the time and cost for the synthesis of large numbers of peptides remain limiting factors. This laboratory has pioneered a number of the seminal advances in combinatorial technology and has been actively involved in their use in the opioid field for the past three years. Two approaches for the identification of individual active compounds from soluble combinatorial libraries have been developed by the principal investigator's laboratory. The first approach, termed a synthetic peptide combinatorial library (SPCL), uses an iterative selection and enhancement process to identify individual peptides. The second approach, termed a Positional Scanning SPCL (PS-SPCL), enables the potential identification of individual compounds of interest directly from the screening data. The feasibility of both of these approaches has been verified using case studies. Chemically diverse libraries, each of which contains tens of millions of individual compounds which can be composed of peptides made of either L-, D- or unnatural amino acids, dimeric or cyclized peptides, as well as similar numbers of non-peptide compounds, will be screened in radioreceptor assays specific for each of the three opioid receptor types, mu, delta, and kappa. Selective compounds identified from the libraries will be tested for agonist or antagonist activities in the guinea-pig ileum and mouse vas deferens bioassays. Highly active and selective agonists and antagonists will also be tested in standard in vivo assays.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA009410-03
Application #
2414606
Study Section
Drug Abuse Biomedical Research Review Committee (DABR)
Program Officer
Hillery, Paul
Project Start
1995-05-01
Project End
1999-04-30
Budget Start
1997-05-01
Budget End
1999-04-30
Support Year
3
Fiscal Year
1997
Total Cost
Indirect Cost
Name
Torrey Pines Institute for Molecular Studies
Department
Type
DUNS #
605758754
City
San Diego
State
CA
Country
United States
Zip Code
Yongye, Austin B; Appel, Jon R; Giulianotti, Marc A et al. (2009) Identification, structure-activity relationships and molecular modeling of potent triamine and piperazine opioid ligands. Bioorg Med Chem 17:5583-97
Houghten, Richard A; Pinilla, Clemencia; Giulianotti, Marc A et al. (2008) Strategies for the use of mixture-based synthetic combinatorial libraries: scaffold ranking, direct testing in vivo, and enhanced deconvolution by computational methods. J Comb Chem 10:3-19
Houghten, Richard A; Dooley, Colette T; Appel, Jon R (2006) In vitro and direct in vivo testing of mixture-based combinatorial libraries for the identification of highly active and specific opiate ligands. AAPS J 8:E371-82
Hoesl, Cornelia E; Ostresh, John M; Houghten, Richard A et al. (2006) Solid phase synthesis of 3,4,7-trisubstituted 4,5,8,9-tetrahydro-3H-imidazo[1,2-a][1,3,5]triazepin-2(7H)-thiones and N-alkyl-4,5,7,8-tetrahydro-3H-imidazo[1,2-a][1,3,5]triazepin-2-amines. J Comb Chem 8:127-31
Hensler, Mary E; Bernstein, Gregory; Nizet, Victor et al. (2006) Pyrrolidine bis-cyclic guanidines with antimicrobial activity against drug-resistant Gram-positive pathogens identified from a mixture-based combinatorial library. Bioorg Med Chem Lett 16:5073-9
Nefzi, Adel; Ostresh, John M; Appel, Jon R et al. (2006) Identification of potent and highly selective chiral tri-amine and tetra-amine mu opioid receptors ligands: an example of lead optimization using mixture-based libraries. Bioorg Med Chem Lett 16:4331-8
Nefzi, Adel; Hoesl, Cornelia E; Pinilla, Clemencia et al. (2006) Synthesis of platinum(II) chiral tetraamine coordination complexes. J Comb Chem 8:780-3
Nefzi, Adel; Santos, Rodegar T (2005) Efficient approaches toward the solid-phase synthesis of new heterocyclic azoniaspiro ring systems: synthesis of tri- and tetrasubstituted 10-oxo- 3,9-diaza-6-azoniaspiro[5.5]undecanes. J Org Chem 70:9622-5
Hoesl, Cornelia E; Nefzi, Adel; Houghten, Richard A (2004) Halogenoalkyl isocyanates as bifunctional reagents in an Aza-Wittig/heterocyclization reaction on the solid phase: efficient entry into new tetracyclic benzimidazole systems. J Comb Chem 6:220-3
Nefzi, Adel; Ostresh, John M; Yu, Yongping et al. (2004) Combinatorial chemistry: libraries from libraries, the art of the diversity-oriented transformation of resin-bound peptides and chiral polyamides to low molecular weight acyclic and heterocyclic compounds. J Org Chem 69:3603-9

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