The long-term broad objectives of this research are to develop reversible antagonists that are selective for specific opioid receptor types and subtypes. Ideally, these ligands should be relatively stable to metabolic inactivation, be able to penetrate the blood-brain barrier, and have high affinity and potency for the target sites. We will employ such ligands as tools to sort out the physiologic and pharmacologic effects produced by endogenous or exogenous opioids. Two classes of bivalent ligands will be synthesized. The first class contains two naltrexone-derived pharmacophores, the second class is characterized by a single antagonist pharmacophore (the """"""""message"""""""") joined to a non-pharmacophore recognition unit designated as the """"""""address"""""""" (a portion of the ligand that confers subtype selectivity). A key feature of both bivalent ligand classes that is expected to play an important role in conferring selectivity is the presence of rigid spacers that connect the recognition units. In the dimeric bivalent ligands, the geometry and length of the rigid spacers will be varied in order to investigate the relationship between the orientation of the rigidly held pharmacophores and opioid antagonist selectivity. These structure-selectivity studies have been designed to provide us with insight into the mode of interaction of such ligands with different opioid receptor types. When such studies suggest that simultaneous occupation of the """"""""message"""""""" and """"""""address"""""""" subsites of a single opioid receptor by a ligand is involved, one of the phamacophores of the dimer will be replaced with the key address moieties that confer selectivity. Such ligands represent the second class of bivalent ligands mentioned above. A total number of 43 target compounds have been proposed for synthesis by four different routes. All target compounds will be tested in three smooth muscle preparations and in the opioid receptor binding assay. Selective ligands will be evaluated further in mice using two different antinociceptive assays. Further studies will be conducted on the kappa antagonist nor-BNI and its congeners to determine if they are acting on a single or multiple populations of kappa opioid receptors.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA002659-07
Application #
3207491
Study Section
Drug Abuse Biomedical Research Review Committee (DABR)
Project Start
1981-09-01
Project End
1992-06-30
Budget Start
1990-07-01
Budget End
1991-06-30
Support Year
7
Fiscal Year
1990
Total Cost
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Type
Schools of Pharmacy
DUNS #
168559177
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
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Levine, A S; Grace, M; Billington, C J et al. (1990) Nor-binaltorphimine decreases deprivation and opioid-induced feeding. Brain Res 534:60-4
Portoghese, A S; Lipkowski, A W; Takemori, A E (1987) Bimorphinans as highly selective, potent kappa opioid receptor antagonists. J Med Chem 30:238-9
Urbanczyk-Lipkowska, Z; Lipkowski, A W; Etter, M C et al. (1987) X-ray crystal structure of the opioid ligand naltrexonazine. J Med Chem 30:1489-94
Portoghese, P S; Larson, D L; Sayre, L M et al. (1986) Opioid agonist and antagonist bivalent ligands. The relationship between spacer length and selectivity at multiple opioid receptors. J Med Chem 29:1855-61
Botros, S; Lipkowski, A W; Takemori, A E et al. (1986) Investigation of the structural requirements for the kappa-selective opioid receptor antagonist, 6 beta,6 beta'-[ethylenebis(oxyethyleneimino)]bis[17-(cyclopropylmethyl)- 4,5 alpha-epoxymorphinan-3,14-diol] (TENA). J Med Chem 29:874-6
Portoghese, P S; Ronsisvalle, G; Larson, D L et al. (1986) Synthesis and opioid antagonist potencies of naltrexamine bivalent ligands with conformationally restricted spacers. J Med Chem 29:1650-3