ORG-26576

Patients with substance use disorders (SUD) are at high risk to die by suicide. So far, the neurobiology of the suicide‐SUD association has not been elucidated. This study aimed to identify potential pharmacological targets among hub genes from brain gene co‐expression networks of individuals with SUD in a suicidal and non‐suicidal context. Post‐mortem samples from the prefrontal cortex of 79 individuals were analyzed. Individuals were classified into the following groups: suicides with SUD (n = 28), suicides without SUD (n = 23), nonsuicides with SUD (n = 9), nonsuicides without SUD (n = 19). Gene expression profiles were evaluated with the Illumina HumanHT‐12 v4 array. Co‐expression networks were constructed in WGCNA using the differentially expressed genes found in the comparisons: (a) suicides with and without SUD and (b) nonsuicides with and without SUD. Hub genes were selected for drug‐gene interaction testing in the DGIdb database. Among drugs interacting with hub genes in suicides we found MAOA inhibitors and dextromethorphan. In the nonsuicide individuals, we found interactions with eglumegad and antipsychotics (olanzapine, clozapine, loxapine). Modafinil was found to interact with genes in both suicides and nonsuicides. These drugs represent possible candidate treatments for patients with SUD with and without suicidal behavior and their study in each context is encouraged.

Asym. total synthesis of (+)-vincadifformine (I) and (+)-ervinceine (II) is reported by utilizing an iminium ion triggered cascade reaction using chiral 3,3-disubstituted piperidine imine and 2,3-disubstituted indole derivatives coupling partner.In the first generation total synthesis, the pivotal imine is prepared in excellent stereoselectivity but in moderate yield involving a Birch reduction-alkylation strategy.Furthermore, to improve upon the synthesis of the decisive imine, the more practical second generation route is devised through a Johnson-Claisen rearrangement to access chiral 3,3-disubstituted piperidinone in excellent yield and stereoselectivity.Apart from synthesizing (+)-vincadifformine, this strategy is also exploited for the first asym. total synthesis of (+)-ervinceine employing an iminium ion mediated cascade reaction.This distinctive strategy simultaneously sets up two new rings, two new stereogenic centers, and three new sigma bonds in a single operation.