Understanding How Youth Search for Mental Health Information Online: A Qualitative Descriptive Study.

The objective of this study was to understand how youth search for mental health information online. Youth partners were engaged at the onset of the project and provided input throughout on the design, conduct and analysis. Individual, semi-structured interviews with Canadian youth with experience searching for mental health information online were conducted. Data collection and reflexive thematic analysis proceeded concurrently. Fourteen youth were interviewed. Four main themes related to how youth search online emerged: mind-set shapes the search process; external factors shape the search process; key attributes of helpful information; and cues affecting trustworthiness of online information. Findings can inform the development of youth-friendly online mental health information that is perceived as helpful and trustworthy by youth. Ensuring youth have access to quality online mental health information, accessible to how they search for it, is critical to the mental health and development of youth.

Design and synthesis of 6-phenylnicotinamide derivatives as antagonists of TRPV1.

6-Phenylnicotinamide (2) was previously identified as a potent TRPV1 antagonist with activity in an in vivo model of inflammatory pain. Optimization of this lead through modification of both the biaryl and heteroaryl components has resulted in the discovery of 6-(4-fluorophenyl)-2-methyl-N-(2-methylbenzothiazol-5-yl)nicotinamide (32; SB-782443) which possesses an excellent overall profile and has been progressed into pre-clinical development.

Characterization of SB-705498, a potent and selective vanilloid receptor-1 (VR1/TRPV1) antagonist that inhibits the capsaicin-, acid-, and heat-mediated activation of the receptor.

Vanilloid receptor-1 (TRPV1) is a nonselective cation channel, predominantly expressed by sensory neurons, which plays a key role in the detection of noxious painful stimuli such as capsaicin, acid, and heat. TRPV1 antagonists may represent novel therapeutic agents for the treatment of a range of conditions including chronic pain, migraine, and gastrointestinal disorders. Here we describe the in vitro pharmacology of N-(2-bromophenyl)-N'-[((R)-1-(5-trifluoromethyl-2-pyridyl)pyrrolidin-3-yl)]urea (SB-705498), a novel TRPV1 antagonist identified by lead optimization of N-(2-bromophenyl)-N'-[2-[ethyl(3-methylphenyl)amino]ethyl]urea (SB-452533), which has now entered clinical trials. Using a Ca(2+)-based fluorometric imaging plate reader (FLIPR) assay, SB-705498 was shown to be a potent competitive antagonist of the capsaicin-mediated activation of the human TRPV1 receptor (pK(i) = 7.6) with activity at rat (pK(i) = 7.5) and guinea pig (pK(i) = 7.3) orthologs. Whole-cell patch-clamp electrophysiology was used to confirm and extend these findings, demonstrating that SB-705498 can potently inhibit the multiple modes of receptor activation that may be relevant to the pathophysiological role of TRPV1 in vivo: SB-705498 caused rapid and reversible inhibition of the capsaicin (IC(50) = 3 nM)-, acid (pH 5.3)-, or heat (50 degrees C; IC(50) = 6 nM)-mediated activation of human TRPV1 (at -70 mV). Interestingly, SB-705498 also showed a degree of voltage dependence, suggesting an effective enhancement of antagonist action at negative potentials such as those that might be encountered in neurons in vivo. The selectivity of SB-705498 was defined by broad receptor profiling and other cellular assays in which it showed little or no activity versus a wide range of ion channels, receptors, and enzymes. SB-705498 therefore represents a potent and selective multimodal TRPV1 antagonist, a pharmacological profile that has contributed to its definition as a suitable drug candidate for clinical development.

TRPV1 antagonist, SB-366791, inhibits glutamatergic synaptic transmission in rat spinal dorsal horn following peripheral inflammation.

The anti-hyperalgesic effects of TRPV1 receptor antagonists are well documented in animal models of pain, however, the precise site of their action is not known. Here we have examined the effects of the selective TRPV1 antagonist SB-366791 on glutamatergic synaptic transmission in substantia gelatinosa using spinal cord slices from either control rats or animals that had undergone a peripheral inflammation induced by intraplantar injection of Freund's complete adjuvant (FCA). In control animals, SB-366791 (30 microM) had no effect on spontaneous excitatory post-synaptic currents (sEPSC) or evoked EPSCs. In slices from FCA-inflamed animals, SB-366791 decreased sEPSC frequency to 66+/-8% of control in 5/10 neurones, and decreased miniature glutamatergic EPSCs (mEPSC) frequency to 63+/-4% of control, in 6/7 neurones; with no significant effect on sEPSC or mEPSC amplitude. Dorsal root evoked EPSCs at C-fibre intensity were reduced to 72+/-6% of control by SB-366791 (30 microM) in 3/4 neurones from FCA-treated animals. In conclusion, SB-366791 inhibited glutamatergic transmission in a subset of neurones via a pre-synaptic mechanism following peripheral inflammation. We hypothesise that during peripheral inflammation spinal TRPV1 becomes tonically active, promoting the synaptic release of glutamate. These results provide evidence for a mechanism by which TRPV1 contributes to inflammatory pain and provides a basis for the understanding of the efficacy of TRPV1 antagonists.

Inhibition of Ih reduces epileptiform activity in rodent hippocampal slices.

Hyperpolarization-activated cyclic nucleotide gated (HCN) ion channels regulate membrane potential, neurotransmitter release, and patterning of synchronized neuronal activity. Currently, there is an intense debate as to whether or not these ion channels play a pro- or anticonvulsant role in vivo. To gain an insight into this question, we have examined how inhibitors of the response mediated by HCN channels (referred to as I(h)) affect epileptiform activity induced in adult hippocampal slices. The archetypal I(h) blocker ZD-7288 produced a concentration-dependent inhibition of both nonsynaptic- (low Ca(2+)/elevated K(+) aCSF) and synaptic- (low Mg(2+) aCSF, elevated K(+) aCSF or convulsant application (bicuculline or pentylenetetrazol)) based epileptiform activities. The IC(50) value for ZD-7288 induced inhibition of epileptiform activity was similar across all forms of epileptiform response and was below concentrations producing nonspecific inhibition of glutamatergic synaptic transmission. Furthermore, capsazepine, which exhibits similar potency to ZD-7288 at inhibiting I(h), failed to inhibit glutamatergic synaptic transmission per se but produced a significant inhibition of bicuculline-induced epileptiform activity. These data suggest that broad spectrum inhibition of I(h) reduces neuronal hyperexcitability in the hippocampus.

Activation of SK channels inhibits epileptiform bursting in hippocampal CA3 neurons.

The role of calcium-activated potassium channels in the regulation of neuronal hyperexcitability, as in epilepsy, is unclear. To examine this issue, we have used the acute hippocampal slice model of epileptiform activity to investigate the effects of an enhancer of SK channel activity, 1-ethyl-benzimidazolinone (EBIO). That EBIO is an SK channel modulator was confirmed by its potentiation of hSK1, hSK2, hSK3 and hIK currents (EC(50) values in the range of 130-870 microM) and its apamin (1 microM) sensitive reduction of the number of action potentials fired in CA3 pyramidal neurons in response to a depolarizing current step. In addition, while EBIO did not significantly affect electrically evoked glutamatergic synaptic transmission, it did inhibit epileptiform activity (IC(50) values in the range of 150-325 microM) induced by (1) modifying the extracellular ionic environment by removing extracellular Mg(2+) or elevating extracellular K(+) from 3.0 to 8.5 mM and (2) disinhibiting the slice using 3 mM pentylenetetrazol or combined application of 10 microM gabazine and 10 microM CGP55845. Furthermore, its inhibitory effect in the full disinhibition model of epileptiform activity (10 microM gabazine + 10 microM CGP55845) was occluded by the SK channel blocker apamin (300 nM-1 microM) which in its own right increased the duration and reduced the frequency of individual epileptiform bursts. In conclusion, compounds that enhance the activation of small conductance Ca(2+) -activated K(+) channels are effective inhibitors of epileptiform activity in vitro.