Oximes short-acting CB1 receptor agonists
| Autor: | Xiaoyu Ma, Srikrishnan Mallipeddi, Michael S. Malamas, Han Zhou, Alexandros Makriyannis, Chandrashekhar Honrao, Othman Benchama, JodiAnne T. Wood, Jimit Girish Raghav |
|---|---|
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Agonist Conformational change Cannabinoid receptor Stereochemistry medicine.drug_class Clinical Biochemistry Pharmaceutical Science Hypothermia 01 natural sciences Biochemistry Mice Structure-Activity Relationship 03 medical and health sciences chemistry.chemical_compound Receptor Cannabinoid CB1 Oximes mental disorders Drug Discovery Cannabinoid receptor type 2 medicine Animals Humans Inverse agonist Potency Molecular Biology Biotransformation G protein-coupled receptor Analgesics Behavior Animal 010405 organic chemistry Chemistry Organic Chemistry Oxime Rats 0104 chemical sciences HEK293 Cells 030104 developmental biology Area Under Curve Molecular Medicine lipids (amino acids peptides and proteins) |
| Zdroj: | Bioorganic & Medicinal Chemistry. 26:4963-4970 |
| ISSN: | 0968-0896 |
| DOI: | 10.1016/j.bmc.2018.08.003 |
| Popis: | New oximes short-acting CB1 agonists were explored by the introduction of an internal oxime and polar groups at the C3 alkyl tail of Δ8-THC. The scope of the research was to drastically alter two important physicochemical properties hydrophobicity (log P) and topological surface area (tPSA) of the compound, which play a critical role in tissue distribution and sequestration (depot effect). Key synthesized analogs demonstrated sub-nanomolar affinity for CB1, marked reduction in hydrophobicity (ClogP∼2.5–3.5 vs 9.09 of Δ8-THC-DMH), and found to function as either agonists (trans-oximes) or neutral antagonists (cis-oximes) in a cAMP functional assay. All oxime analogs showed comparable affinity at the CB2 receptor, but surprisingly they were found to function as inverse agonists for CB2. In behavioral studies (i.e. analgesia, hypothermia) trans-oxime 8a exhibited a predictable fast onset (∼20 min) and short duration of pharmacological action (∼180 min), in contrast to the very prolonged duration of Δ8-THC-DMH (>24 h), thus limiting the potential for severe psychotropic side-effects associated with persistent activation of the CB1 receptor. We have conducted 100 ns molecular dynamic (MD) simulations of CB1 complexes with AM11542 (CB1 agonist) and both trans-8a and cis-8b isomeric oximes. These studies revealed that the C3 alkyl tail of cis-8b orientated within the CB1 binding pocket in a manner that triggered a conformational change that stabilized the CB1 receptor at its inactive-state (antagonistic functional effect). In contrast, the trans-8a isomer’s conformation was coincided with that of the AM11542 CB1 agonist-bound structure, stabilizing the CB1 receptor at the active-state (agonistic functional effect). We have selected oxime trans-8a based on its potency for CB1, and favorable pharmacodynamic profile, such as fast onset and predictable duration of pharmacological action, for evaluation in pre-clinical models of anorexia nervosa. |
| Databáze: | OpenAIRE |
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