Synthesis of new opioid derivatives with a propellane skeleton and their pharmacology: Part 1

Design and synthesis ofC3-symmetric molecules bearing propellane moieties via cyclotrimerization and a ring-closing metathesis sequence

“…The design of propellanes demands unique synthetic methods and these include: manganese or palladium-catalyzed transformations [ 10 ], the Diels–Alder (DA) reaction [ 11 – 12 ], and rearrangement of spiro-ketones, nucleophilic substitutions of alkenes, and photochemical addition reactions. Multicomponent reactions (MCRs) are also used for the synthesis of hetero-propellanes [ 13 – 14 ]. Recently, heterocyclic propellanes have been reviewed [ 15 – 16 ].…”

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

“…Quinolinopropellane 3a with the Ncyclopropylmethyl group had the highest binding affinity for the DOR, while N-(1-hydroxycyclopropylmethyl) derivative 3b showed the highest selectivity for the DOR, although its binding affinity for the DOR was slightly decreased compared with that of 3a. Although a propellane 1 derivative with the N-methyl substituent was reported to be a strong binder to the MOR (K i = 3.6 nM) with 122-and 71-fold greater selectivities over the DOR and KOR, 13 respectively, N-methylquinolinopropellane 3d exerted low but evident selectivity for the DOR.…”

“…2) as a novel message skeleton. 13 The propellane 1 bound to the MOR, DOR, and KOR with binding affinities (K i ) of 58.2 nM, 448 nM, and 17.4 nM, respectively. These results prompted us to develop novel ligands with the propellane skeleton.…”

Synthesis of novel triplet drugs with 1,3,5-trioxazatriquinane skeletons and their pharmacologies. 3: Synthesis of novel triplet drugs with the bis(epoxymethano) or bis(dimethylepoxymethano) structure (double-capped triplet)

“…This substituent effect was also observed in other morphinan derivatives. [8][9][10][11] Among compounds with N-Me substituent, SYK-385 (19b) was the most selective for the l receptor and was more selective than KNT-123, 6 which was a capped homotriplet drug with an N-Me group and was reported to show the highest selectivity for the l receptor over the j receptor among the reported l-selective nonpeptide ligands. [12][13][14][15] The affinities of compounds with bulky substituents (iBu or Bn group) on the nitrogen were very low.…”