ABSTRACT
The number of opioid-related overdose deaths and individuals that have suffered from opioid use disorders have significantly increased over the last 30 years. FDA approved maintenance therapies to treat opioid use disorder may successfully curb drug craving and prevent relapse but harbor adverse effects that reduce patient compliance. This has created a need for new chemical entities with improved patient experience. Previously our group reported a novel lead compound, NAT, a mu-opioid receptor antagonist that potently antagonized the antinociception of morphine and showed significant blood-brain barrier permeability. However, NAT belongs to thiophene containing compounds which are known structural alerts for potential oxidative metabolism. To overcome this, 15 NAT derivatives with various substituents at the 5'-position of the thiophene ring were designed and their structure-activity relationships were studied. These derivatives were characterized for their binding affinity, selectivity, and functional activity at the mu opioid receptor and assessed for their ability to antagonize the antinociceptive effects of morphine in vivo. Compound 12 showed retention of the basic pharmacological attributes of NAT while improving the withdrawal effects that were experienced in opioid-dependent mice. Further studies will be conducted to fully characterize compound 12 to examine whether it would serve as a new lead for opioid use disorder treatment and management.
Subject(s)
Receptors, Opioid, mu , Animals , Structure-Activity Relationship , Mice , Receptors, Opioid, mu/metabolism , Receptors, Opioid, mu/antagonists & inhibitors , Humans , Molecular Structure , Thiophenes/chemistry , Thiophenes/pharmacology , Thiophenes/chemical synthesis , Thiophenes/therapeutic use , Male , Dose-Response Relationship, Drug , Analgesics, Opioid/pharmacology , Analgesics, Opioid/chemistry , Narcotic Antagonists/pharmacology , Narcotic Antagonists/chemistry , Morphine/pharmacologyABSTRACT
We present the synthesis and characterization of a new family of expanded meso-alkylidenyl (2,6-pyri)porphyrinoids bearing multiple exocyclic double bonds at the meso-positions. The synthesis was accomplished by using mixed pyrrole condensation. Similar to meso-alkylidenyl porphyrinoids, this study revealed that pyriporphyrinoids do not possess a porphyrin-like, global-aromatic character. The synthesized 2,6-pyripentaphyrin 1 displays selective ratiometric sensing of pyrophosphate anion in organic solvent.
ABSTRACT
Treatment of meso-malonylidene-(m-benzi)porphyrin and meso-malonylidene-(m-benzi)pentaphyrin with Pd(ii), Au(iii), Ni(ii) and Ag(i) afforded the corresponding metal complexes. The synthesized metal complexes were characterized by spectroscopy including single crystal X-ray, NMR and mass spectrometry. Most metal complexes were stable in solution. The metal complexes showed strong absorption in the near IR region.
