The overall goal of our continuing interdisciplinary studies of opiates is the design of useful analgesics which produce little or no respiratory depression, sedation or physical dependence. To this end, we shall design two different types of analogs I) delta-selective nonpeptide agonists and II) nonselective ligands with agonism and antagonism at different opiate receptors. To accomplish the first major goal, we shall: a) verify the delta-selectivity of peptide/nonpeptide agonists/antagonists; b) provide further validation of their in vivo profiles, specifically: antinociception, respiratory depression, sedation and physical dependence liability; c) design delta-selective peptide surrogates/mimetics using our recently characterized determinants of cyclic peptide recognition of the delta receptor; d) synthesis and assessment of compounds for receptor affinity, in vitro activity and ultimately in vivo action to assess their therapeutic usefulness; e) identify and characterize molecular determinants of recognition and activation at the delta receptor of fused ring indole opioids using computational chemistry; f) identify novel compounds that satisfy molecular determinants by searching chemical databases, acquire and assess their in vitro and in vivo pharmacological profile. The second major goal of our studies is the design of novel nonselective ligands with diverse combinations of agonism and antagonism at the mu, delta and kappa1 receptors. To this end, we shall: a) for a set of 12 known nonselective mixed agonists/antagonists, experimentally determine a direct correlation between in vitro profile and in vivo behavior for the four endpoints of interest; b) use this correspondence to identify the combination of agonism and antagonism which leads to the desired in vivo profile; c) use combined experimental and theoretical techniques to identify determinants of recognition and activation at the mu and kappa1 receptors and combine these with similar results for the delta receptor; d) validate the molecular determinants for recognition and activation deduced for each receptor by testing their ability to account for the known behavior of analogs not used in hypothesis development; e) use the hypotheses to design new analogs with the mixed agonist/antagonist profile identified as related to the desired in vivo endpoints. The experimental studies include: a) determination of receptor affinities at mu, delta, kappa1 and kappa2 receptors; b) thermodynamic analysis of binding to mu, delta, and kappa1 receptors, to gain insights into the molecular interactions involved in the recognition step; c) assessment of receptor activation by determination of the inhibition of field stimulated muscle contractions in guinea pig ileum (mu and kappa) and mouse vas deferens (delta); d) assessment of the in vivo profile relevant to our therapeutic goals: i) antinociception using tail- flick and paw-pressure assays, ii) sedation, by determination of locomotor activity, iii) respiratory depression, using blood gases as indicators, iv) physical dependence liability, by observing jumping, weight loss and hypothermia upon antagonist challenge after chronic treatment. The theoretical studies include: a) effective search strategies combining nested rotation, molecular dynamics simulations and energy optimization using molecular mechanics and semiempirical quantum mechanics to determine the accessible conformational domains; b) selection of the bioactive form for each receptor and determination of the most appropriate environment for its formation; c) calculation of physical and electronic properties, i.e. conformation dependent hydrophobicities, polarizabilities, proton and electron donating and accepting abilities that could be determinants of receptor recognition and activation.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA002622-16
Application #
2116619
Study Section
Drug Abuse Biomedical Research Review Committee (DABR)
Project Start
1980-03-01
Project End
1997-03-31
Budget Start
1995-04-01
Budget End
1996-03-31
Support Year
16
Fiscal Year
1995
Total Cost
Indirect Cost
Name
Molecular Research Institute
Department
Type
DUNS #
017430633
City
Palo Alto
State
CA
Country
United States
Zip Code
94303
Morgan, Judith K; Shaw, Daniel S; Olino, Thomas M et al. (2016) History of Depression and Frontostriatal Connectivity During Reward Processing in Late Adolescent Boys. J Clin Child Adolesc Psychol 45:59-68
Martin, Monica J; Conger, Rand D; Sitnick, Stephanie L et al. (2015) Reducing Risk for Substance Use by Economically Disadvantaged Young Men: Positive Family Environments and Pathways to Educational Attainment. Child Dev 86:1719-37
Morgan, Judith K; Shaw, Daniel S; Forbes, Erika E (2015) Fearfulness moderates the link between childhood social withdrawal and adolescent reward response. Soc Cogn Affect Neurosci 10:761-8
Morgan, Judith K; Shaw, Daniel S; Forbes, Erika E (2014) Maternal depression and warmth during childhood predict age 20 neural response to reward. J Am Acad Child Adolesc Psychiatry 53:108-117.e1
Filizola, M; Laakkonen, L; Loew, G H (1999) 3D modeling, ligand binding and activation studies of the cloned mouse delta, mu;and kappa opioid receptors. Protein Eng 12:927-42
Huang, P; Kim, S; Loew, G (1997) Development of a common 3D pharmacophore for delta-opioid recognition from peptides and non-peptides using a novel computer program. J Comput Aided Mol Des 11:21-8
Maguire, P A; Loew, G H (1996) Thermodynamics of ligand binding to the cloned delta-opioid receptor. Eur J Pharmacol 318:505-9
Alkorta, I; Loew, G H (1996) A 3D model of the delta opioid receptor and ligand-receptor complexes. Protein Eng 9:573-83
Chen, S W; Maguire, P A; Davies, M F et al. (1996) Evidence for mu1-opioid receptor involvement in fentanyl-mediated respiratory depression. Eur J Pharmacol 312:241-4
Chao, T M; Perez, J J; Loew, G H (1996) Characterization of the bioactive form of linear peptide antagonists at the omega-opioid receptor. Biopolymers 38:759-68

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