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Buprenorphine C7‐Esters with Improved Nociceptin Receptor Agonist Potency as Analgesics
Author(s) -
Olson Keith Mathew,
CamiKobeci Gerta,
Husbands Stephen M.,
Traynor John R.
Publication year - 2019
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2019.33.1_supplement.663.16
Subject(s) - nop , nociceptin receptor , agonist , chemistry , potency , pharmacology , partial agonist , buprenorphine , opioid , μ opioid receptor , receptor , analgesic , medicine , opioid peptide , biochemistry , in vitro
There is an urgent need for analgesics with reduced abuse liability, withdrawal, respiratory depression and constipation to treat chronic pain patients. While clinical opiates produce analgesia and associated side effects through Mu Opioid Receptor (MOR) agonist activity, preclinical evidence indicates activity at the Kappa‐ (KOR), Delta‐ (DOR), and Nociception Receptors (NOP) subtypes can minimize side effects. Compounds displaying NOP agonist and weak MOR partial agonist activity produce antinociception with minimal abuse liability in primates and therefore are desirable therapeutic target. In the present study we evaluated buprenorphine analogues with C7 ester substituents for opioid receptor affinity by competition binding assay and for function using the [ 35 S]‐GTPgS assay at MOR, NOP, DOR and KOR. Compounds showed a nearly 1000‐fold range in binding and [ 35 S]‐GTPgS activity at NOP, ranging from low nanomolar to micromolar. One compound, containing a phenyl ester at C7, and lacking a keto group at C6, showed the highest potency NOP activity (EC 50 = 0.97 +/− 0.22 nM, E MAX = 47% +/− 11) with weak partial agonist potency at MOR (EC 50 = 3.9 +/− 1.3 nM, E MAX = 23% +/− 7). Since this compound has less MOR agonist efficacy than buprenorphine, it would be predicted to have minimal abuse liability. The series also showed a synergistic relationship in NOP activity between the C7 functional group and the C6 oxidation state. For example, the presence of a keto group at C6 decreased NOP potency significantly (EC 50 = 164 +/− 51 nM, E MAX = 47% +/− 9). This pattern was observed with numerous C7 functional groups. All compounds in the series were putative antagonists at DOR and KOR as they bound with high affinity but did stimulate significant activity in the [ 35 S]‐GTPgS assay. This series of compounds provides different degrees of partial agonism at MOR and NOP and should help to determine the minimal MOR activity necessary for effective antinociception while minimizing potential abuse liability. Support or Funding Information Supported by R01 DA07315 and 035316. This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .