Discovery of spirofused piperazine and diazepane amides as selective histamine-3 antagonists with in vivo efficacy in a mouse model of cognition.

A new series of potent and selective histamine-3 receptor (H3R) antagonists was identified on the basis of an azaspiro[2.5]octane carboxamide scaffold. Many scaffold modifications were largely tolerated, resulting in nanomolar-potent compounds in the H3R functional assay. Exemplar compound 6s demonstrated a selective profile against a panel of 144 secondary pharmacological receptors, with activity at only σ2 (62% at 10 µM). Compound 6s demonstrated free-plasma exposures above the IC50 (∼50×) with a brain-to-plasma ratio of ∼3 following intravenous dosing in mice. At three doses tested in the mouse novel object recognition model (1, 3, and 10 mg/kg s.c.), 6s demonstrated a statistically significant response compared with the control group. This series represents a new scaffold of H3 receptor antagonists that demonstrates in vivo exposure and efficacy in an animal model of cognition.

Azepines and piperidines with dual norepinephrine dopamine uptake inhibition and antidepressant activity.

Herein, we describe the discovery of inhibitors of norepinephrine (NET) and dopamine (DAT) transporters with reduced activity relative to serotonin transporters (SERT). Two compounds, 8b and 21a, along with nomifensine were tested in a rodent receptor occupancy study and demonstrated dose-dependent displacement of radiolabeled NET and DAT ligands. These compounds were efficacious in a rat forced swim assay (model of depression) and also had activity in rat spontaneous locomotion assay.

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. Bursting patterns of dopamine neuron activity remained largely unchanged by application of AZD0328. In vivo microdialysis in awake rats showed an increase in extracellular prefrontal cortical dopamine in response to low doses of AZD0328. Compound-stimulated dopamine release showed an inverted dose effect relation that was maximal at the lowest dose tested (0.00178 mg/kg). Peak extracellular dopamine levels were reached 2h after dosing with AZD0328. Acquisition of operant responding with delayed reinforcement in rats was dose dependently enhanced by AZD0328 with a plateau effect measured at 0.003 mg/kg. This effect was blocked by pre-treatment of animals with the selective alpha7 antagonist methyllycaconitine. AZD0328 improved novel object recognition in mice over a broad range of doses (0.00178-1.78 mg/kg) and the compound effect was found to be absent in homozygous alpha7 KO animals. Together, these data indicate that selective interaction with alpha7 NNRs by AZD0328 selectively enhances midbrain dopaminergic neuronal activity causing an enhancement of cortical dopamine levels; these neurochemical changes likely, underlie the positive behavioral responses observed in two different animal models. Our results suggest selective alpha7 NNR agonists may have significant therapeutic utility in neurologic and psychiatric indications where cognitive deficits and dopamine neuron dysfunction co-exist.

Postnatal epigenetic influences on seizure susceptibility in seizure-prone versus seizure-resistant rat strains.

The creation of seizure-prone (Fast) and seizure-resistant (Slow) rat strains via selective breeding implies genetic control of relative seizure vulnerability, yet ample data also advocates an environmental contribution. To investigate potential environmental underpinnings to the differential seizure sensitivities in these strains, the authors compared amygdala kindling profiles in adult male Fast and Slow rats raised by (a) their own mother, (b) a foster mother from the same strain, or (c) a foster mother from the opposing strain. Ultimately, strain-specific kindling profiles were not normalized by cross-fostering. Instead, both strains became more seizure-prone regardless of maternal affiliation (i.e., cross-fostered groups from both strains kindled faster than uncrossed controls). Interhemispheric seizure spread was also facilitated in cross-fostered Slow rat groups and was associated with increased commissural cross-sectional areas, giving them a Fast-like profile. It is important to note, however, that all Fast groups remained significantly more seizure-prone than Slow groups, suggesting that although the postnatal environment strongly influenced seizure disposition in both strains, it did not wholly account for their relative dispositions. Investigation into mechanisms fundamental to cross-fostering-induced seizure facilitation should help prevent postnatal worsening of pathology in already seizure-prone individuals.