Sigma receptors are potential therapeutic targets for substance abuse. Small molecule ligands targeting sigma receptors may influence actions of drugs of abuse like cocaine and ethanol by reducing conditioned place preference and drug self-administration. Novel high affinity sigma receptor ligands can be developed using the multicomponent assembly process to generate diverse heterocyclic scaffolds. Going forward, efforts will focus on improving potency and selectivity of lead compounds, determining the best sigma receptor subtype to target, advancing leads into mouse models, and validating sigma receptors as targets for treating addiction.
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Sigma Receptors: Potential Targets for Treating Substance Abuse
1. Sigma Receptors:
Potential Therapeutic Targets For Substance Abuse
Figure from NIDA Research Report Series: Comorbidity: Addiction and Other Mental Illnesses. NIH Publication Number 10-5771, 2008.
James J. Sahn, Ph.D.
Texas Institute for Drug and Diagnostic Development
University of Texas at Austin
SIGMA Rs
2. We Need Drugs That Treat Substance Abuse!
1. Mesangeau, C. et. al. J. Med. Chem. 2008, 51, 1482.
2. Mersy, D. J. Am. Fam. Physician 2003, 7, 1529.
The Problem: There is an unmet need for medicines that treat drug and
alcohol abuse
A Potential Solution: Small molecule targeting of the sigma receptor
Sigma receptors influence the actions of
psychostimulants and alcohol
Sigma receptors modulate neurotransmitter
systems relevant to the actions of drugs of abuse
4. I. Introduction to Sigma Receptors:
Notable Sigma Drugs / Ligands
1. Volz, H. –P.; Stoll, K. D. Pharmacopsychiatry 2004, 37, Suppl 3: S214-S220.
2. Moller, H. J. et. al. J. Clin. Psychopharmacol. 2001, 21, 59.
3. Mach, R. H. et. al. Nat. Commun. 2011, 2:380.
5. II. Sigma Receptor Ligands and Drugs of Abuse:
Mechanisms Through Which SRs Influence the Actions of Drugs of Abuse
Matsumoto, R. R. et al. Sigma Receptors and Drug abuse. In Sigma Receptors: Chemistry, Cell Biology and Clinical Implications; Ed.
Matsumoto. R. R.; Bowen, W. D; Su, T, -P., Springer: New York, 2007; pp 315-336.
SIGMA Rs
6. II. Sigma Receptor Ligands and Drugs of Abuse:
Cocaine
1. Banister, S. D.; Kassiou, M. Curr. Pharm. Des. 2012, 18, 884.
2. Mesangeau, C. et. al. J. Med. Chem. 2008, 51, 1482.
3. Matsumoto, R. R. et. al. Neuropharmacology 49 2005, 638.
4. Figure from: www.accuscan-usa.com.
No approved medications for treating cocaine abuse
Pretreatment with a sigma receptor antagonist reduced:
Conditioned Place Preference (CPP)
Locomotor stimulation
Toxic effects
Dopamine and DAT depletion
Cocaine
7. II. Sigma Receptor Ligands: Potential Therapeutics for Substance Abuse.
5/18/20131. Horan, B. et. al. Eur. J. Pharm. 2001, 426, R1.
2. Brammer, M. K. et. al. Eur. J. Pharmacol. 2006, 553, 141.
7
(-) nicotine
s1 agonist blocked CPP acquisition
MDMA
s1 antagonist and locomotor stimulation
8. II. Sigma Receptor Ligands and Drugs of Abuse:
Ethanol
1. Bhutada, P. S. et. al. Behav. Pharmacol. 2012, 23, 25.
2. Maurice, T. et. al. Pharmacol. Biochem. Behav. 2003, 74, 869.
Ethanol does not directly bind to the sigma receptor
Decreased Conditioned Place Preference in Rats
Decreased ethanol self-administration in both Sardinian alcohol
preferring and acutely withdrawn ethanol dependent rats
Non-dependent controls showed no changes in mean ethanol or water
intake.
9. II. Sigma Receptor Ligands and Drugs of Abuse
Take-Home Message
Sigma receptor ligands can influence the actions of abused
substances, even those that do not bind to sigma receptors.
Sigma antagonists act via specific modulation of sigma
receptors, as opposed to a general suppressive effect.
10. III. Novel, High Affinity Sigma Receptor Ligands:
Privileged Scaffolds
“a single molecular framework able to provide diverse ligands for
receptors”. B. E. Evans, 1988
Privileged scaffolds in drugs
1. Evans, B. E.; Rittle, K. E.; et. al. J. Med. Chem. 1988, 31, 2235.
2. Ariens, E. J.; Beld, A. J.; et. al. The Receptors. A Comprehensive Treatise; O’ Brien, R. D., Ed.; Plenum Press: New York, 1979; p. 33.
3. Andrews, P. R.; Lloyd, E. J. Med. Res. Rev. 1982, 2, 355.
4. Welsch, M. E.; Snyder, S. A.; Stockwell, B. R. Curr. Opin. Chem. Biol. 2010, 14, 347.
5. Veber, D. F.; Johnson, S. R.; Cheng, H. –Y.; Smith, B. R.; Ward, K. W.; Kopple, K. D. J. Med. Chem. 2002, 45, 2615.
Privileged scaffolds tend to be “drug-like”
11. III. Novel, High Affinity Sigma Receptor Ligands:
The Multicomponent Assembly Process (MCAP) for Generating Diverse
Heterocyclic Scaffolds
12. III. Novel, High Affinity Sigma Receptor Ligands:
The Multicomponent Assembly Process (MCAP) for Generating Diverse
Heterocyclic Scaffolds
1. Sahn, J. J.; Su, J.; Martin, S. F. Org. Lett. 2011, 13, 2590.
2. Sahn, J. J.; Martin, S. F. Tetrahedron Lett. 2011, 52, 6855.
3. Granger, B. A.; Kaneda, K.; Martin, S. F. Org. Lett. 2011, 13, 4542.
13. III. Novel, High Affinity Sigma Receptor Ligands:
Binding Affinity (Ki)
Cheng-Prusoff Equation
14. Glennon/Ablordeppey Pharmacophore Model
For High Affinity Sigma 1 Binding
Ablordeppey, S.Y.; El-Ashmawy, M. B.; Fischer, J. B.; Glennon, R. A. Eur. J. Med. Chem. 1998, 33, 625.
15. Future Objectives
Continue to improve potency and selectivity of lead
compounds
Determine which SR subtype should be targeted for the
best therapeutic response
Advance lead SR drugs into mouse models
Validate the SR as a target for the treatment of
psychostimulant and alcohol addiction