We have launched a broad program to study the relationship of opioid structure to biological function. Our general approach for computer aided drug design commences with the selection of target molecules based on molecular mechanics simulations. These molecules are then synthesized and characterized through troscopy, more extensive computer simulations and biological assays to develop structure/function relationships. As a result of prior work in this area, we have proposed a model, to explain the receptor selectivity of constrained opioids that we have designed and synthesized. Peptidomimetic modifications to the peptide backbone of enkephalin analogs allow us to test our conformational model of receptor selectivity. Specific target molecules are Tyr-c[D-gA2bu-mGly-rD-Phe- mLeu] and Tyr-c[D-gA2bu-mGly-gPhe-mLeu]. These represent a natural extension of our earlier work with retro-inverso modifications. The dipeptide analog 3-aminocyclopentane carboxylic acid (beta-Ac-'c) will be in enkephalin analogs. The follows our successful efforts in incorporating, 2 aminocyclopentane carboxylic acid (beta-Ac5c) in morphiceptin analogs to manipulate receptor specificity. challenge of discriminating among the four possible stereoisomers necessitate broad application of techniques such as NOESY, ROESY, extended COSY, and DISCO, as well as extensive computer simulations. Our past success in employing carrier conjugates of catecholamines to increase activity and specificity encourages similar experiments with enkephalins. Thus we propose to launch an integrated program for the sis and characterization of novel enkephalin conjugates. We have hopes of inducing not only receptor specific binding, but also of uncovering fundamental principles of membrane-peptide interaction. All final products emanating from our computer aided drug designs will be tested for biological activity. We have established collaborations with Dr. Peter Schiller at the Clinical Research Institute of Montreal for in vitro assays and Dr. Tony Yaksh here at UCSD for in vivo tests.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA006254-04
Application #
2118559
Study Section
Special Emphasis Panel (SRCD (04))
Project Start
1989-09-30
Project End
1994-08-31
Budget Start
1992-09-01
Budget End
1993-08-31
Support Year
4
Fiscal Year
1992
Total Cost
Indirect Cost
Name
University of California San Diego
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
077758407
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Ro, S; Zhu, Q; Lee, C W et al. (1995) Highly potent side chain-main chain cyclized dermorphin-deltorphin analogues: an integrated approach including synthesis, bioassays, NMR spectroscopy and molecular modelling. J Pept Sci 1:157-74
Yaksh, T L; Malmberg, A B; Ro, S et al. (1995) Characterization of the spinal antinociceptive activity of constrained peptidomimetic opioids. J Pharmacol Exp Ther 275:63-72
Yamazaki, T; Ro, S; Goodman, M et al. (1993) A topochemical approach to explain morphiceptin bioactivity. J Med Chem 36:708-19
Goodman, M; Ro, S; Osapay, G et al. (1993) The molecular basis of opioid potency and selectivity: morphiceptins, dermorphins, deltorphins, and enkephalins. NIDA Res Monogr 134:195-209
Said-Nejad, O E; Felder, E R; Mierke, D F et al. (1992) 14-membered cyclic opioids related to dermorphin and their partially retro-inverso modified analogues. I. Synthesis and biological activity. Int J Pept Protein Res 39:145-60
Goodman, M; Ro, S; Yamazaki, T et al. (1992) Topochemical design of bioactive peptides and peptidomimetics. Bioorg Khim 18:1375-93
Yamazaki, T; Mierke, D F; Said-Nejad, O E et al. (1992) 14-membered cyclic opioids related to dermorphin and their partially retro-inverso modified analogues. II. Preferred conformations in solution as studied by 1H-NMR spectroscopy. Int J Pept Protein Res 39:161-81
Yamazaki, T; Probsti, A; Schiller, P W et al. (1991) Biological and conformational studies of [Val4]morphiceptin and [D-Val4]morphiceptin analogs incorporating cis-2-aminocyclopentane carboxylic acid as a peptidomimetic for proline. Int J Pept Protein Res 37:364-81
Yamazaki, T; Ro, S; Goodman, M (1991) Topochemical analysis of morphiceptin and dermorphin bioactivities. Biochem Biophys Res Commun 181:664-70
Yaksh, T L; Jang, J D; Nishiuchi, Y et al. (1991) The utility of 2-hydroxypropyl-beta-cyclodextrin as a vehicle for the intracerebral and intrathecal administration of drugs. Life Sci 48:623-33