Pharmacological Inhibition of PARP6 Triggers Multipolar Spindle Formation and Elicits Therapeutic Effects in Breast Cancer.

: PARP proteins represent a class of post-translational modification enzymes with diverse cellular functions. Targeting PARPs has proven to be efficacious clinically, but exploration of the therapeutic potential of PARP inhibition has been limited to targeting poly(ADP-ribose) generating PARP, including PARP1/2/3 and tankyrases. The cancer-related functions of mono(ADP-ribose) generating PARP, including PARP6, remain largely uncharacterized.

Broad analgesic activity of a novel, selective M1 agonist.

Although the muscarinic receptor family has long been a source of potentially compelling targets for small molecule drug discovery, it was difficult to achieve agonist selectivity within the family. A new class of M1 muscarinic agonists has emerged, and these compounds have been characterized as agonists that activate the receptor at an allosteric site. Members of this class of M1 agonists have been shown to be selective across the muscarinic receptors.

Quetiapine and its metabolite norquetiapine: translation from in vitro pharmacology to in vivo efficacy in rodent models.

Background And Purpose: Quetiapine has a range of clinical activity distinct from other atypical antipsychotic drugs, demonstrating efficacy as monotherapy in bipolar depression, major depressive disorder and generalized anxiety disorder. The neuropharmacological mechanisms underlying this clinical profile are not completely understood; however, the major active metabolite, norquetiapine, has been shown to have a distinct in vitro pharmacological profile consistent with a broad therapeutic range and may contribute to the clinical profile of quetiapine.

Experimental Approach: We evaluated quetiapine and norquetiapine, using in vitro binding and functional assays of targets known to be associated with antidepressant and anxiolytic drug actions and compared these activities with a representative range of established antipsychotics and antidepressants.

Quantification of the interrelationships of receptor pharmacologies within a tricyclic privileged structural scaffold through application of modified forward selection.

Many neuropsychiatric drugs interact with more than one molecular target, and therapeutic indices might be improved by prospectively designing compounds with profiles optimized against a combination of targets. The dibenzo-epine scaffold is considered a privileged structure, and this scaffold has been explored rigorously in the search for potential novel neuropharmacologic treatments. Members of this chemical class are known to interact with many receptors and transporters, particularly those of the biogenic amine class.

Synthesis and SAR of aminothiazole fused benzazepines as selective dopamine D2 partial agonists.

Dopamine (D(2)) partial agonists (D2PAs) have been regarded as a potential treatment for schizophrenia patients with expected better side effect profiles than currently marketed antipsychotics. Herein we report the synthesis and SAR of a series of aminothiazole fused benzazepines as selective D(2) partial agonists. These compounds have good selectivity, CNS drug-like properties and tunable D(2) partial agonism.

Preclinical pharmacology and pharmacokinetics of AZD3783, a selective 5-hydroxytryptamine 1B receptor antagonist.

The preclinical pharmacology and pharmacokinetic properties of (2R)-6-methoxy-8-(4-methylpiperazin-1-yl)-N-(4-morpholin-4-ylphenyl)chromane-2-carboxamide (AZD3783), a potent 5-hydroxytryptamine 1B (5-HT(1B)) receptor antagonist, were characterized as part of translational pharmacokinetic/pharmacodynamic hypothesis testing in human clinical trials. The affinity of AZD3783 to the 5-HT(1B) receptor was measured in vitro by using membrane preparations containing recombinant human or guinea pig 5-HT(1B) receptors and in native guinea pig brain tissue. In vivo antagonist potency of AZD3783 for the 5HT(1B) receptor was investigated by measuring the blockade of 5-HT(1B) agonist-induced guinea pig hypothermia.

Absence of direct effects on the dopamine D2 receptor by mGluR2/3-selective receptor agonists LY 354,740 and LY 379,268.

We previously reported the absence of high-affinity binding of the group II metabotropic glutamate receptor agonists LY 354,740 and LY 379,268 to the D2L dopamine receptor. A rebuttal to our findings has since been reported (see Introduction section); this study represents our response. Analysis by LCMS of LY 354,740 and LY 379,268 used in this study revealed the correct molecular mass for these compounds.

D2 receptor occupancy in conscious rat brain is not significantly distinguished with [3H]-MNPA, [3H]-(+)-PHNO, and [3H]-raclopride.

Positron emission tomography (PET) antagonist ligands such as [(11)C]-raclopride are commonly used to study dopamine D2 receptor (D2) binding of antipsychotics. It has been suggested that agonist radioligands bind preferentially to the high-affinity state of D2 receptor and may provide a more relevant means of assessing D2 occupancy. The main objective of this study was to determine if D2 receptor occupancy (RO) could be differentiated with agonist and antagonist radioligands in vivo.

Selective alpha7 nicotinic receptor activation by AZD0328 enhances cortical dopamine release and improves learning and attentional processes.

AZD0328, a novel spirofuropyridine neuronal nicotinic receptor partial agonist, was used to investigate the role of alpha7 neuronal nicotinic receptor (NNR) activation in the modulation of midbrain dopamine neuron function, cortical dopamine release and on two behavioral tasks known to be dependent on optimal levels of cortical dopamine. In vivo recordings from area 10 (ventral tegmental area) in rat brain showed an increased firing of putative dopamine neurons in response to low (0.00138 mg/kg) doses of AZD0328.

Low affinity use-dependent NMDA receptor antagonists show promise for clinical development.

The success of the low affinity use-dependent NMDA receptor antagonists to reach clinical trials can be readily attributed to their wider margins of safety and lack of neurotoxicity at higher doses. Several mechanistic differences distinguish the low affinity from the high affinity use-dependent antagonists: 1) Differential regional affinities for the various NMDA receptor subtypes; 2) The static receptor blockade due to the faster on/off rate receptor kinetics which limit, but do not totally prevent the amount of Ca+2 entry into the cell during glutamate-induced depolarization; and 3) Rapid egress of the compounds from the ion channel during recovery resulting in less membrane trapping between transmission pulses. Advanced clinical trials are in progress for the following indications: epilepsy, stroke, head trauma, tardive dyskinesia, pain plus Parkinson's, Huntington's and Alzheimer's diseases.

Long-term functional end points following middle cerebral artery occlusion in the rat.

The purpose of the present study was to assess the magnitude and stability of a number of functional deficits in rats subjected to occlusion of the middle cerebral artery (MCAO). Three groups of rats, treated with 90-min, 120-min, or sham occlusion were used in functional studies for 22 weeks following surgery. The following tests were used: methamphetamine-induced rotation, the staircase test, acquisition of operant responding, running-wheel behavior, and performance of operant differential reinforcement of a low-rate responding (DRL) schedule of reinforcement.

Homogeneity of regional brain lead concentrations.

It has been proposed that the neurobiological basis of many of the behavioral manifestations arising in response to Pb exposure may be due to selective vulnerability of particular brain regions, such as hippocampus, a region in which preferential accumulation has been reported in some studies. However, these findings have not been invariant and, in fact, have been found to vary with dosing parameters. This study examined potential regional accumulation of Pb in brain following postnatal exposure of rats to Pb via nursing dams consuming Pb acetate solutions of 0, 100, 350, 1000, or 2000 ppm.

Time course of postnatal lead-induced changes in dopamine receptors and their relationship to changes in dopamine sensitivity.

Although alterations in dopaminergic function represent a potential neurochemical basis of Pb-induced behavioral deficits, the impact of postnatal Pb exposure on DA systems has not been adequately delineated. This study examined the effects of postnatal Pb exposure, across a broad range of concentrations, on the ontogeny of both D1 and D2 DA (dopamine) receptors in striatum and nucleus accumbens. Rat pups were exposed to Pb from 0-21 days of age via lactating dams consuming solutions of 0, 100, 350, 1000 or 2000 ppm Pb acetate.

Apparent mediation of the stimulus properties of a low dose of quinpirole by dopaminergic autoreceptors.

This study examined the hypothesis that, if the stimulus properties of the D2 agonist quinpirole (QUIN) were mediated by autoreceptors, then pharmacological treatments engendering a decline in dopamine (DA) release and consequent decrease in postsynaptic DA receptor stimulation should result in QUIN-appropriate responding; those that activate postsynaptic receptors should result in saline-appropriate responding. In rats trained to discriminate 0.05 mg/kg of QUIN from saline using standard operant drug discrimination procedures, QUIN (up to the training dose), two other putative D2 autoreceptor agonists (low-dose apomorphine and N-propylnorapomorphine), the DA depeleter alpha-methyl-p-tyrosine (AMPT) and the D1 antagonist SCH 23390 all produced primarily QUIN-lever responding.

Functional alterations in dopamine systems assessed using drug discrimination procedures.

Numerous studies have suggested that Pb-induced perturbations of dopamine (DA) systems and DA functions could underlie the behavioral impairments attributed to Pb exposure. However, the precise nature of the effects of Pb on DA systems, either at the receptor/biochemical level or at the behavioral level have never been precisely delineated, much less interrelated. Substantial advances in the understanding of DA neuropharmacology provide new opportunities to more precisely elaborate Pb-induced changes in DA systems and DA function.

Postnatal lead exposure induces supersensitivity to the stimulus properties of a D2-D3 agonist.

To examine the impact of lead (Pb) exposure during the ontogeny of dopaminergic (DA) systems on resultant DA function, rats were exposed postnatally (0-21 days of age) via the lactating dam to 0, 100 or 350 ppm Pb acetate in drinking water. At 2 months of age, the postnatally Pb-exposed rats were trained to discriminate the stimulus properties of either the D1 receptor agonist SKF38393 (6.0 mg/kg) or the D2-D3 receptor family subtype agonist quinpirole (0.

Lead retards development of Drosophila melanogaster.

1. Lead (Pb) is a ubiquitous environmental toxicant which has been reported to have growth-retarding effects. That premise was examined in the current study of the effects of developmental exposure to Pb on the maturation of the fruitfly Drosophila melanogaster.

Low level lead exposure increases sensitivity to the stimulus properties of dopamine D1 and D2 agonists.

To examine the impact of Pb exposure on dopaminergic (DA) function, weanling rats were chronically exposed to 0, 50 or 250 ppm Pb acetate in drinking water. At 3 months of age, the rats were trained to discriminate the stimulus properties of either the D1 agonist SKF38393 (3.0 mg/kg i.

Behavioral manifestations of prolonged lead exposure initiated at different stages of the life cycle: II. Delayed spatial alternation.

Since both Pb exposure and aging have been associated with alterations in memory functions, this study compared the effects of Pb exposure initiated at early, middle and later stages of the life cycle on delayed spatial alternation performance. Young (21 day old), adult (8 mon old) and old (16 mon old) rats were exposed for a total duration of 8.5 mon to 0, 2 or 10 mg Pb acetate/kg/day (young rats) or 0, 1.

Behavioral differentiation of the stimulus properties of a dopaminergic D1 agonist from a D2 agonist.

This study examined the hypothesis that the stimulus properties of a dopaminergic D1 agonist should be functionally discriminable from those of a D2 agonist. Rats were trained in a two-lever food-reinforced drug discrimination paradigm to discriminate either the D1 agonist SKF 38393 from apomorphine (SKF/APO), SKF from saline (SKF/SAL) or apomorphine from saline (APO/SAL), at an APO dose previously established to have D2-mediated stimulus properties. Results showed the SKF/APO discrimination to be readily acquired.