Discovery and Characterization of ML398, a Potent and Selective Antagonist of the D4 Receptor with in Vivo Activity.

Herein, we report the structure-activity relationship of a chiral morpholine-based scaffold, which led to the identification of a potent and selective dopamine 4 (D4) receptor antagonist. The 4-chlorobenzyl moiety was identified, and the compound was designated an MLPCN probe molecule, ML398. ML398 is potent against the D4 receptor with IC50 = 130 nM and K i = 36 nM and shows no activity against the other dopamine receptors tested (>20 μM against D1, D2S, D2L, D3, and D5).

Towards the Total Synthesis of Marineosin A: Construction of the Macrocyclic Pyrrole and an Advanced, Functionalized Spiroaminal Model.

Herein, we describe the enantioselective construction of the 12-membered macrocyclic pyrrole core of marineosin A in 5.1% overall yield from ()-propylene oxide. The route features a key Stetter reaction to install a 1,4-diketone, which is then subjected to Paal-Knorr pyrrole synthesis and ring closing metathesis (RCM) to afford macrocycle A divergence point in the synthetic scheme also enabled access to a highly functionalized spiroaminal model system via an acid-mediated hydroxyketoamide cyclization strategy.

Spiroaminal Model Systems of the Marineosins with Final Step Pyrrole Incorporation.

In this Letter, we describe a short, 6-step enantioselective route to spiroaminal lactam model systems reminiscent of marineosins A and B has been developed starting from either ()- or ()-hydroxysuccinic acid, respectively, in ~9% overall yield. This route enables late stage incorporation of the pyrrole ring at C5 via nucleophilic displacement of an iminium triflate salt.