Positive allosteric modulators of the delta-opioid receptor
AssigneeBristol-Myers Squibb Company
InventorsNeil T. Burford, Ying Han, Martyn N. Banks, Litao Zhang, Samuel Gerritz, Andrew Alt
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Abstract
Described are the discovery, synthesis and pharmacological characterization of δ-opioid receptor-selective positive allosteric modulators (δ PAMs). These δ PAMs may increase the affinity and/or efficacy of the orthosteric agonists leu-enkephalin and SNC80, as measured by β-arrestin recruitment and adenylyl cyclase inhibition. The compounds may be useful pharmacological tools to probe the molecular pharmacology of the δ receptor and to explore the therapeutic potential of δ PAMs in diseases such as chronic pain and depression.
Claims12
A method of screening to identify delta-opioid receptor positive allosteric modulators comprising the steps of:
- (a) adding a positive allosteric modulator test compound and a low concentration of a delta-selective orthosteric agonist to cells;
- (b) measuring the effect of said delta-selective orthosteric agonist and said test compound on said cells;
- and
- (c) identifying said test compound as being a positive allosteric modulator as evidenced by a decrease in the positive allosteric agonist activity of said test compound.
A method of screening to identify delta-opioid receptor negative allosteric modulators comprising the steps of:
- (i) adding a negative allosteric modulator test compound and a high concentration of a delta-selective orthosteric agonist to cells;
- (ii) measuring the effect of said delta-selective orthosteric agonist and said test compound on said cells;
- and
- (iii) identifying said test compound as being a negative allosteric modulator as evidenced by a decrease in the negative allosteric agonist activity of said test compound.
A method of treating pain in a patient in need thereof comprising administering to the patient a compound which is a positive allosteric modulator for the delta-opioid receptor.
A method of treating pain in a patient in need thereof comprising administering to the patient a compound which is a positive allosteric modulator for the delta-opioid receptor in combination with another compound which is an orthosteric agonist for the delta-opioid receptor.
A method of modulating the delta-opioid receptor comprising contacting the receptor with a compound that is effective to provide an increase in the receptor function in the presence of orthosteric exogenous or endogenous agonist.
Dependencies are inferred from the claim text.