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Evaluation of N-substituent structural variations in opioid receptor profile of LP1.
- Source :
-
Bioorganic & Medicinal Chemistry . Jun2016, Vol. 24 Issue 12, p2832-2842. 11p. - Publication Year :
- 2016
-
Abstract
- The benzomorphan scaffold has great potential as lead structure and the nature of the N -substituent is able to influence affinity, potency, and efficacy at all three opioid receptors. Building upon these considerations, we synthesized a new series of LP1 analogues by introducing naphthyl or heteroaromatic rings in propanamide side chain of its N -substituent ( 9 – 15 ). In vitro competition-binding assays in HEK293 cells stably expressing MOR, DOR or KOR showed that in compound 9 the 1-naphthyl ring led to the retention of MOR affinity ( K i MOR = 38 ± 4 nM) displaying good selectivity versus DOR and KOR. In the electrically stimulated GPI, compound 9 was inactive as agonist but produced an antagonist potency value (pA 2 ) of 8.6 in presence of MOR agonist DAMGO. Moreover, subcutaneously administered it antagonized the antinociceptive effects of morphine with an AD 50 = 2.0 mg/kg in mouse-tail flick test. Modeling studies on MOR revealed that compound 9 fit very well in the binding pocket but in a different way in respect to the agonist LP1. Probably the replacement of its N -substituent on the III, IV and V TM domains reflects an antagonist behavior. Therefore, compound 9 could represent a potential lead to further develop antagonists as valid therapeutic agents and useful pharmacological tools to study opioid receptor function. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 09680896
- Volume :
- 24
- Issue :
- 12
- Database :
- Academic Search Index
- Journal :
- Bioorganic & Medicinal Chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 115800280
- Full Text :
- https://doi.org/10.1016/j.bmc.2016.05.005