Synthesis and SAR Study of Opioid Receptor Ligands: Mono‐ and Bis‐Indolomorphinans

Abstract

Mono- and bis-indolomorphinans were synthesized through a multi-step synthetic approach from the alkaloid, thebaine, to further explore the C-ring SAR (structure-activity relationship) of morphinan scaffold. Both mono-indoles displayed good binding affinity and selectivity for the delta receptor, with compound 6b possessed the highest K(i) value of 1.45 nm at this receptor. Bisindolomorphinans 7a,b did not have appreciable affinity for both delta and kappa receptors, but moderate binding at the mu receptor was observed. Functional assays indicated that the newly synthesized mono-indole 6b was delta-agonist, opposite to the delta-antagonist profile of naltrindole. Bisindoles 7a,b were mu-agonists. This work further confirms that the phenol component in opioids is essential for higher binding to the opioid receptors. The different binding ability, receptor selectivity, and the functional activity profiles of naltrindole 2, monoindole 6b, and bisindole 7b clearly indicated that they interact with the opioid receptors in different modes.

Rapid access to morphinones: removal of 4,5-ether bridge with Pd-catalyzed triflate reduction

“…As shown, the alternate route for the synthesis of morphinones 17–19 is accomplished in two steps (from intermediates 9, 11 and 12 ) compared to the four steps needed for the synthesis of 18 and 19 and six steps for 17 via the traditional route 7,8,11,12,15. The new method offers a faster, more efficient alternative and utilizes less harsh reaction conditions/reagents than that required for the traditional process.…”

Promotion of Chemical Reactions by a Grid in a Shear Mixing Layer

“…General procedure for the preparation of aminothiazolomorphinans 13 a, 13 b, 7, and 8. Two‐step procedure: A solution of bromine (1.0 equiv) in AcOH (2 mL) was added slowly to a solution of 12 a 7, 20 or 12 b 7b, 20b in AcOH (5 mL) and two drops of HBr (48 %) at room temperature. The solution was heated at 60 °C for 3 h before one portion of thiourea (2.0 equiv) was added.…”

A modular and divergent approach for the total synthesis of Elaeocarpus alkaloids

“…With the B ring being directed in an orthogonal orientation to the D ring, compounds 5 (cis-cis in C7/8/9) and 2 (cis-trans) exhibit a higher binding affinity than 1 (2.7 and 13.6 μM vs. 86.4 μM), whose B ring is located almost in the same plane as the D ring (transtrans). Recognizing that basic nitrogen and extended aromatic substituents are important features for selective DOR binders, 15 the ideal scaffolds from this class would be molecules possessing both cis-cis configuration and an aromatic A ring, e.g., 8-epi-1, which is unnatural and not easy to construct according to Danishefsky's studies. 11,16 In addition, some newly isolated natural products, such as 3, 4, 6 and 7, have not been synthesized yet.…”