T-type calcium channels have been implicated in many behaviorally important neurophysiological processes, and altered channel activity has been linked to the pathophysiology of neurological disorders such as insomnia, epilepsy, Parkinson's disease, depression, schizophrenia, and pain. We have previously identified a number of potent and selective T-type channel antagonists (Barrow et al., 2007;Shipe et al., 2008;. Here we describe the properties of the antagonist, assessed in patchclamp experiments. TTA-A2 blocks T-type channels (Ca v 3.1, 3.2, 3.3) voltage dependently and with high potency (IC 50 ϳ100 nM). Stimulation at 3 Hz revealed additional use dependence of inhibition. A hyperpolarized shift of the channel availability curve and delayed channel recovery from inactivation suggest that the compound preferentially interacts with and stabilizes inactivated channels. The compound showed a ϳ300-fold selectivity for Ca v 3 channels over high-voltage activated calcium channels. Inhibitory effects on native T-type currents were confirmed in brain slice recordings from the dorsal lateral geniculate nucleus and the subthalamic nucleus. Furthermore, we demonstrate that in vivo T-type channel inhibition by TTA-A2 suppresses active wake and promotes slow-wave sleep in wild-type mice but not in mice lacking both Ca v 3.1 and Ca v 3.3, suggesting the selective effect of TTA-A2 on recurrent thalamocortical network activity. The discovery of the potent and selective T-type channel antagonist TTA-A2 has enabled us to study the in vivo effects of pharmacological T-channel inhibition on arousal in mice, and it will help to explore the validity of these channels as potential drug targets for sleep-related and other neurological diseases.
The epidemics of obesity and metabolic disorders have well-recognized health and economic burdens. Pharmacologic treatments for these diseases remain unsatisfactory with respect to both efficacy and side-effect profiles. Here, we have identified a potential central role for T-type calcium channels in regulating body weight maintenance and sleep. Previously, it was shown that mice lacking Ca V 3.1 T-type calcium channels have altered sleep/wake activity. We found that these mice were also resistant to high-fat diet-induced weight gain, without changes in food intake or sensitivity to high-fat diet-induced disruptions of diurnal rhythm. Administration of a potent and selective antagonist of T-type calcium channels, TTA-A2, to normal-weight animals prior to the inactive phase acutely increased sleep, decreased body core temperature, and prevented high-fat diet-induced weight gain. Administration of TTA-A2 to obese rodents reduced body weight and fat mass while concurrently increasing lean muscle mass. These effects likely result from better alignment of diurnal feeding patterns with daily changes in circadian physiology and potentially an increased metabolic rate during the active phase. Together, these studies reveal what we believe to be a previously unknown role for T-type calcium channels in the regulation of sleep and weight maintenance and suggest the potential for a novel therapeutic approach to treating obesity.
α-Thiocarbocations generated from Pummerer reactions of several
o-imido sulfoxides were
intercepted by adjacent carbonyl groups to produce
α-amido-substituted isobenzofurans as transient
intermediates. When an olefinic tether was present, intramolecular
Diels−Alder cycloaddition
occurred followed by a ring-opening−elimination sequence that
produced an N-acyliminium ion.
Deprotonation of the iminium ion led to oxindole derivatives in
good yields. When the iminium
ion contained both a blocking substituent, such as a carbomethoxy
group, as well as an activated
aromatic π-tether, the N-acyliminium ion intermediate
underwent stereoselective spirocyclization
to afford cis-3,4-benzoerythrinane or homoerythrinane
derivatives in good yield. The overall triple
cascade sequence represents an efficient one-pot approach toward the
erythrina skeleton in which
the spirocyclic ABC skeleton is assembled in a single operation.
The scope and limitations of the
triple cascade were explored by varying both the olefinic and
nucleophilic tethers. The required
sulfoxide precursors for these Pummerer-induced transformations were
easily synthesized starting
from 2-[(ethylthio)methyl]benzoic acid. The tandem
Pummerer/Diels−Alder/N-acyliminium ion
cyclization was used for the synthesis of indoloisoquinoline
38. Since compound 38 was
converted
to 47 which, in turn, was transformed into erysotramidine
(2), its preparation represents an
extraordinarily facile, formal synthesis of this member of the
Erythrina alkaloid family.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.