Search for α3β₂/₃γ2 subtype selective ligands that are stable on human liver microsomes.

Selective modulation of specific benzodiazepine receptor (BzR) gamma amino butyric acid-A (GABA(A)) receptor ion channels has been identified as an important method for separating out the variety of pharmacological effects elicited by BzR-related drugs. Importantly, it has been demonstrated that both α2β(2/3)γ2 (α2BzR) and α3BzR (and/or α2/α3) BzR subtype selective ligands exhibit anxiolytic effects with little or no sedation. Previously we have identified several such ligands; however, three of our parent ligands exhibited significant metabolic liability in rodents in the form of a labile ester group.

trans-2-(2,5-Dimethoxy-4-iodophenyl)cyclopropylamine and trans-2-(2,5-dimethoxy-4-bromophenyl)cyclopropylamine as potent agonists for the 5-HT(2) receptor family.

A strategy to replace the ethylamine side chain of 2,5-dimethoxy-4-iodoamphetamine (DOI, 1a), and 2,5-dimethoxy-4-bromoamphetamine (DOB, 1b) with a cyclopropylamine moiety was successful in leading to compounds with high affinity at the 5-HT(2) family of receptors; and the more potent stereoisomer of the cyclopropane analogues had the expected (-)-(1R,2S)-configuration. Screening for affinity at various serotonin receptor subtypes, however, revealed that the cyclopropane congeners also had increased affinity at several sites in addition to the 5-HT(2A) and 5-HT(2B) receptors. Therefore, at appropriate doses - although (-)-4 and (-)-5 may be useful as tools to probe 5-HT(2) receptor function - one would need to be mindful that their selectivity for 5-HT(2A) receptors is somewhat less than for DOI itself.

Pharmacosynthetics: Reimagining the pharmacogenetic approach.

Pharmacology, in its broadest interpretation, is defined as the study of the interaction between physiological entities and drugs. In modern neuropsychopharmacology, this interaction is viewed as the drug itself on one side and signal transducer (receptor), the signal transduction cascade (effector proteins, second messengers), the cellular response (transcriptional regulation, activity modulation), the organ response (brain circuitry modulation), and, finally, the whole organism response (behavior) on the other. In other words, pharmacology has structured itself around the idea that the exogenous molecule (the drug) encodes a "signal" leading to everything on the other side including, in extreme renditions, a physiological response.

Quantitative analysis of focused a-to-I RNA editing sites by ultra-high-throughput sequencing in psychiatric disorders.

A-to-I RNA editing is a post-transcriptional modification of single nucleotides in RNA by adenosine deamination, which thereby diversifies the gene products encoded in the genome. Thousands of potential RNA editing sites have been identified by recent studies (e.g.

Marine algal toxin azaspiracid is an open-state blocker of hERG potassium channels.

Azaspiracids (AZA) are polyether marine dinoflagellate toxins that accumulate in shellfish and represent an emerging human health risk. Although human exposure is primarily manifested by severe and protracted diarrhea, this toxin class has been shown to be highly cytotoxic, a teratogen to developing fish, and a possible carcinogen in mice. Until now, AZA's molecular target has not yet been determined.

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 D(2) receptor (D(2)R) agonists UNC9975 (44) and UNC9994 (36), which have robust in vivo antipsychotic drug-like activities.

Rational Drug Design Leading to the Identification of a Potent 5-HT(2C) Agonist Lacking 5-HT(2B) Activity.

The 5-HT(2C) receptor is an attractive drug target in the quest for new therapeutics to treat a variety of human disorders. We have previously undertaken a structural optimization campaign that has led to some potent and moderately selective 5-HT(2C) receptor agonists. After expanding our structure-function library, we were able to combine our datasets so as to allow the design of compounds of improved selectivity and potency.

Moderate chemical modifications of WAY-100635 improve the selectivity for 5-HT1A versus D4 receptors.

The selectivity for 5-HT(1A) versus D(4) receptors is significantly increased when the basic side chain of WAY-100635 is replaced by a 4-phenylpiperazine (3e) or a 4-phenyl-1,2,3,6-tetrahydropyridine moiety (3i). The 4-phenyl-1,2,3,6-tetrahydropyridine compounds (3i-l) have a higher affinity for 5-HT(1A) receptors than do the corresponding unsubstituted phenylpiperazine analogues (3e-h). Compounds 3e and 3i appear to be selective for 5-HT(1A) receptors over other relevant receptors and still behave as neutral antagonists.

Identifying mechanism-of-action targets for drugs and probes.

Notwithstanding their key roles in therapy and as biological probes, 7% of approved drugs are purported to have no known primary target, and up to 18% lack a well-defined mechanism of action. Using a chemoinformatics approach, we sought to "de-orphanize" drugs that lack primary targets. Surprisingly, targets could be easily predicted for many: Whereas these targets were not known to us nor to the common databases, most could be confirmed by literature search, leaving only 13 Food and Drug Administration-approved drugs with unknown targets; the number of drugs without molecular targets likely is far fewer than reported.

Life beyond kinases: structure-based discovery of sorafenib as nanomolar antagonist of 5-HT receptors.

Of great interest in recent years has been computationally predicting the novel polypharmacology of drug molecules. Here, we applied an "induced-fit" protocol to improve the homology models of 5-HT(2A) receptor, and we assessed the quality of these models in retrospective virtual screening. Subsequently, we computationally screened the FDA approved drug molecules against the best induced-fit 5-HT(2A) models and chose six top scoring hits for experimental assays.

Structure of the nociceptin/orphanin FQ receptor in complex with a peptide mimetic.

Members of the opioid receptor family of G-protein-coupled receptors (GPCRs) are found throughout the peripheral and central nervous system, where they have key roles in nociception and analgesia. Unlike the 'classical' opioid receptors, δ, κ and μ (δ-OR, κ-OR and μ-OR), which were delineated by pharmacological criteria in the 1970s and 1980s, the nociceptin/orphanin FQ (N/OFQ) peptide receptor (NOP, also known as ORL-1) was discovered relatively recently by molecular cloning and characterization of an orphan GPCR. Although it shares high sequence similarity with classical opioid GPCR subtypes (∼60%), NOP has a markedly distinct pharmacology, featuring activation by the endogenous peptide N/OFQ, and unique selectivity for exogenous ligands.

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-HT(6)R), a known target for cognition enhancers, and employed these models for virtual screening to identify putative 5-HT(6)R actives.

Benzothiazoles as probes for the 5HT1A receptor and the serotonin transporter (SERT): a search for new dual-acting agents as potential antidepressants.

The synthesis and evaluation of several benzothiazole-based compounds are described in an attempt to identify novel dual-acting 5HT(1A) receptor and SERT inhibitors as new antidepressants. Binding affinities at the 5HT(1A) receptor and the serotonin transporter do not appear to be congruent and other areas of the binding sites would need to be explored in order to improve binding simultaneously at both sites. Compounds 20 and 23 show moderate binding affinity at the 5HT(1A) receptor and the SERT site and thus, have the potential to be further explored as dual-acting agents.

Bis-spirolabdane diterpenoids from Leonotis nepetaefolia.

Ten new bis-spirolabdane diterpenoids, leonepetaefolins A-E (1, 3, 5, 7, 9) and 15-epi-leonepetaefolins A-E (2, 4, 6, 8, 10), together with eight known labdane diterpenoids (11-18) as well as two known flavonoids, apigenin and cirsiliol, were isolated from the leaves of Leonotis nepetaefolia. The structures of the new compounds were determined on the basis of 1D- and 2D-NMR experiments including (1)H, (13)C, DEPT, (1)H-(1)H COSY, HSQC, HMBC, and NOESY. The absolute configuration of an epimeric mixture of 1 and 2 was determined by X-ray crystallographic analysis.

Labdane diterpenoids from Leonotis leonurus.

Three known (leoleorins A-C) and eight hitherto unknown (leoleorins D-J and 16-epi-leoleorin F) labdane diterpenoids, were isolated from leaves of Leonotis leonurus. The absolute configurations of leoleorins A and D were established by X-ray crystallographic analyses. In a competitive binding assay, all isolated compounds showed inhibition in excess of 50% at various CNS receptors.

Generation of a synthetic memory trace.

We investigated the effect of activating a competing, artificially generated, neural representation on encoding of contextual fear memory in mice. We used a c-fos-based transgenic approach to introduce the hM(3)D(q) DREADD receptor (designer receptor exclusively activated by designer drug) into neurons naturally activated by sensory experience. Neural activity could then be specifically and inducibly increased in the hM(3)D(q)-expressing neurons by an exogenous ligand.

Structure-activity relationship studies of SYA 013, a homopiperazine analog of haloperidol.

Structure-activity relationship studies on 4-(4-(4-chlorophenyl)-1,4-diazepan-1-yl)-1-(4-fluorophenyl)butan-1-one (SYA 013), a homopiperazine analog of haloperidol has resulted in an understanding of the effect of structural modifications on binding affinity at dopamine and serotonin receptor subtypes. Further exploration, using bioisosteric replacement strategies has led to the identification of several new agents including compounds 7, 8, 11 and 12 which satisfy the initial criteria for further exploration as new antipsychotic agents. In addition, compound 18, a D(3) selective tropanol, has been identified as having the potential for further optimization into a useful drug which may combat neuropsychiatric diseases.

Multi-receptor drug design: Haloperidol as a scaffold for the design and synthesis of atypical antipsychotic agents.

Using haloperidol as a scaffold, new agents were designed to investigate the structural contributions of various groups to binding at CNS receptors associated with atypical antipsychotic pharmacology. It is clear that each pharmacophoric group, the butyrophenone, the piperidine and the 4-chlorophenyl moieties contributes to changes in binding to the receptors of interest. This strategy has resulted in the identification of several new agents, compounds 16, 18, 19, 23, 24 and 25, with binding profiles which satisfy our stated criteria for agents to act as potential atypical antipsychotics.

4-Aminoethylpiperazinyl aryl ketones with 5-HT₁A/5-HT₇ selectivity.

The well-known 5-HT(1A)/5-HT(7) selectivity issue was tackled by a new series of 4-aminoethylpiperazinyl aryl ketones (1a-1l) specifically designed to distinguish the two hydrophobic sites centered at the anchoring salt bridge. The 4-aminoethylpiperazinyl aryl ketones showed a wide spectrum of activity and selectivity for the 5-HT receptors depending on the type of the hydrophobic groups attached at the aryl piperazinyl ketone scaffold. Docking study of the most active compounds against 5-HT(7)R and 5-HT(1A)R revealed that both receptors have two hydrophobic pockets around the anchoring salt bridge.

Topoisomerase inhibitors unsilence the dormant allele of Ube3a in neurons.

Angelman syndrome is a severe neurodevelopmental disorder caused by deletion or mutation of the maternal allele of the ubiquitin protein ligase E3A (UBE3A). In neurons, the paternal allele of UBE3A is intact but epigenetically silenced, raising the possibility that Angelman syndrome could be treated by activating this silenced allele to restore functional UBE3A protein. Using an unbiased, high-content screen in primary cortical neurons from mice, we identify twelve topoisomerase I inhibitors and four topoisomerase II inhibitors that unsilence the paternal Ube3a allele.

Chemical informatics and target identification in a zebrafish phenotypic screen.

Target identification is a core challenge in chemical genetics. Here we use chemical similarity to computationally predict the targets of 586 compounds that were active in a zebrafish behavioral assay. Among 20 predictions tested, 11 compounds had activities ranging from 1 nM to 10,000 nM on the predicted targets.