Chemocentric Informatics Approach to Drug Discovery: Identification and Experimental Validation of Selective Estrogen Receptor Modulators as Ligands of 5-Hydroxytryptamine-6 Receptors and as Potential Cognition Enhancers

We have devised a chemocentric informatics methodology for drug discovery integrating independent approaches to mining biomolecular databases. As a proof of concept, we have searched for novel putative cognition enhancers. First, we generated Quantitative Structure–Activity Relationship (QSAR) models of compounds binding to 5-hydroxytryptamine-6 receptor (5-HT₆R), a known target for cognition enhancers, and employed these models for virtual screening to identify putative 5-HT₆R actives. Second, we queried chemogenomics data from the Connectivity Map (http://www.broad.mit.edu/cmap/) with the gene expression profile signatures of Alzheimer’s disease patients to identify compounds putatively linked to the disease. Thirteen common hits were tested in 5-HT₆R radioligand binding assays and ten were confirmed as actives. Four of them were known selective estrogen receptor modulators that were never reported as 5-HT₆R ligands. Furthermore, nine of the confirmed actives were reported elsewhere to have memory-enhancing effects. The approaches discussed herein can be used broadly to identify novel drug–target–disease associations

Molecular Targets Profiled.

<p>Molecular Targets Profiled.</p

Mesh plot summarizing pharmacology of 3 novel PCP analogues.

<p>Shown in three dimensional mesh plot format are the pKi values of the three novel PCP analogues (3-MeO-PCE, 3-MeO-phencyclidine and 4-MeO-phencyclidine; 1, 2 and 3 respectively) against a panel of 56 molecular targets.</p

Bis-spirolabdane Diterpenoids from <i>Leonotis nepetaefolia</i>

Ten new bis-spirolabdane diterpenoids, leonepetaefolins A–E (<b>1</b>, <b>3</b>, <b>5</b>, <b>7</b>, <b>9</b>) and 15-<i>epi</i>-leonepetaefolins A–E (<b>2</b>, <b>4</b>, <b>6</b>, <b>8</b>, <b>10</b>), together with eight known labdane diterpenoids (<b>11</b>–<b>18</b>) as well as two known flavonoids, apigenin and cirsiliol, were isolated from the leaves of <i>Leonotis nepetaefolia</i>. The structures of the new compounds were determined on the basis of 1D- and 2D-NMR experiments including ¹H, ¹³C, DEPT, ¹H–¹H COSY, HSQC, HMBC, and NOESY. The absolute configuration of an epimeric mixture of <b>1</b> and <b>2</b> was determined by X-ray crystallographic analysis. The compounds isolated were evaluated for their binding propensity in several CNS G-protein-coupled receptor assays in vitro

Structure–Functional Selectivity Relationship Studies of β‑Arrestin-Biased Dopamine D₂ Receptor Agonists

Functionally selective G protein-coupled receptor (GPCR) ligands, which differentially modulate canonical and noncanonical signaling, are extremely useful for elucidating key signal transduction pathways essential for both the therapeutic actions and side effects of drugs. However, few such ligands have been created, and very little purposeful attention has been devoted to studying what we term: “structure–functional selectivity relationships” (SFSR). We recently disclosed the first β-arrestin-biased dopamine D₂ receptor (D₂R) agonists UNC9975 (<b>44</b>) and UNC9994 (<b>36</b>), which have robust in vivo antipsychotic drug-like activities. Here we report the first comprehensive SFSR studies focused on exploring four regions of the aripiprazole scaffold, which resulted in the discovery of these β-arrestin-biased D₂R agonists. These studies provide a successful proof-of-concept for how functionally selective ligands can be discovered

Orally Active Adenosine A₁ Receptor Agonists with Antinociceptive Effects in Mice

Adenosine A₁ receptor (A₁AR) agonists have antinociceptive effects in multiple preclinical models of acute and chronic pain. Although numerous A₁AR agonists have been developed, clinical applications of these agents have been hampered by their cardiovascular side effects. Herein we report a series of novel A₁AR agonists, some of which are structurally related to adenosine 5′-monophosphate (5′-AMP), a naturally occurring nucleotide that itself activates A₁AR. These novel compounds potently activate A₁AR in several orthogonal in vitro assays and are subtype selective for A₁AR over A_2AAR, A_2BAR, and A₃AR. Among them, UNC32A (<b>3a</b>) is orally active and has dose-dependent antinociceptive effects in wild-type mice. The antinociceptive effects of <b>3a</b> were completely abolished in A₁AR knockout mice, revealing a strict dependence on A₁AR for activity. The apparent lack of cardiovascular side effects when administered orally and high affinity (<i>K</i>_i of 36 nM for the human A₁AR) make this compound potentially suitable as a therapeutic

Probability of occurrence of the observed number of DNVs in genes recurrently hit by non-synonymous de novo SNVs.

<p>Probability of occurrence of the observed number of DNVs in genes recurrently hit by non-synonymous de novo SNVs.</p

List of the 49 validated <i>de novo</i> variants.

<p>List of the 49 validated <i>de novo</i> variants.</p