Design and synthesis of quinolinopropellane derivatives with selective δ opioid receptor agonism

Abstract

Indolopropellane 2 was reported to show almost no binding affinity to the δ opioid receptor (DOR) in spite of the fact that 2 has both the propellane fundamental skeleton (message part) with binding ability to the opioid receptors and a possible DOR address structure (indole moiety). We developed the working hypothesis that almost no binding affinity of 2 to the DOR would be derived from its possibly stable bent conformer. To enable the propellane skeleton to adopt an extended conformation which would reasonably interact with the DOR, quinolinopropellanes 3a-d were designed which had an additional pharmacophore, quinoline nitrogen. The calculated binding free energies of ligand-DOR complexes strongly supported our working hypothesis. The synthesized quinolinopropellane 3a was a selective DOR full agonist, confirming our working hypothesis and the results of in silico investigation.

Diversity-Oriented Synthesis toward Fused and Bridged Benzobicyclic Piperidin(on)es

“…Because indeno­[2,1- c ]­piperidines were recognized as pharmacologically valuable compounds, and some effort has been devoted to their synthesis, we decided to check the possible synthesis of C-4-functionalized indeno­[2,1- c ]­piperidines, using enolizable properties of the carbonyl group in lactams 1 or the thiocarbonyl group in thiolactams 2 . Such functionalized thiolactams obtained could be reduced under the above optimized conditions.…”

Friedlӓnder's synthesis of quinolines as a pivotal step in the development of bioactive heterocyclic derivatives in the current era of medicinal chemistry

“…Quinolinopropellanes (256) were constructed from propellanes (253), which gave a δ opioid receptor agonism pharmacophore from Friedländer condensation (Scheme 55) and was reported by Hiroshi Nagase (Nagase et al, 2014) and group. The synthesized quinolinopropellane 256a was a selective DOR full agonist, confirming results of in silico investigation, quinolinopropellane 256a with the N-cyclopropylmethyl (CPM) group have high binding affinity for the DOR, while N-(1-hydroxycyclopropylmethyl) (−1-OH-CPM) derivative 256b shows the higher selectivity for the DOR, even its binding affinity for the DOR was somewhat decreased compared with that of 256a.…”

Modification of magnetic mesoporous N-doped silica nanospheres by CuO NPs: a highly efficient catalyst for the multicomponent synthesis of some propellane indeno indole derivatives

“…Also, the chemical and biological activity of propellanes has turned them into attractive structures. [6][7][8][9][10][11][12][13] Some domino multicomponent reactions for the preparation of [3.3.3] propellanes have been reported.…”