cis-1,2-Cyclohexanediol (L3) has been shown to be an efficient and versatile bidentate O-donor ligand that provides a highly active Cu-catalytic system. It was more effective than diols such as ...trans-1,2-cyclohexanediol or ethylene glycol. This commercially available cis-1,2-cyclohexanediol ligand facilitated the Cu-catalyzed cross-coupling reactions of alkyl, aryl, or heterocyclic thiols with either alkyl, aryl, heterocyclic, or substituted vinyl halides. This new catalytic system promoted the mild and efficient stereo- and regiospecific synthesis of biologically important vinyl sulfides. The yields obtained using electron-rich substituted vinyl sulfides with this catalyst system are generally 75−98%. Most importantly, this singular catalyst system is extremely versatile and provides entry into a wide range of sulfides. This method is particularly noteworthy given its mild reaction conditions, simplicity, generality, and exceptional level of functional group tolerance.
A mild and efficient method for the copper-catalyzed formation of vinylic carbon−sulfur bonds has been developed. The desired vinyl sulfides are obtained in good to excellent yields, with full ...retention of stereochemistry. This method is particularly noteworthy given its mild reaction conditions, simplicity, and generality, as well as low cost of the catalyst system.
It is well-known that N b-benzyltryptophan alkyl esters undergo the Pictet−Spengler reaction with aldehydes to furnish both cis- and trans-1,2,3,4-tetrahydro-β-carbolines, with the trans isomer ...predominating. Epimerization at C-1 took place under acidic conditions to produce, exclusively, the thermodynamically more stable trans diastereomer via internal asymmetric induction. Recent kinetic experiments provided insight into the cis to trans epimerization mechanism involved in the Pictet−Spengler reaction of 1,2,3-trisubsituted tetrahydro-β-carbolines. Since the epimerization reaction had been shown to be sensitive to electronic effects at C-1, the rate data for a series of 1-phenyl-substituted 1,2,3,4-tetrahydro-β-carbolines was investigated via a Hammett study. Analysis of the data supported the presence of a positively charged intermediate with a ρ value of −1.4, although the existence of an iminium ion intermediate or a carbocationic intermediate could not be determined from this data alone. Analysis of the rate of epimerization demonstrated first-order kinetics with respect to TFA following the initial protonation of the substrate. This observation was consistent with the formation of a doubly protonated intermediate as the rate-determining step in the carbocation-mediated cis to trans epimerization process. In addition, the observed first-order rate dependence was inconsistent with the retro-Pictet−Spengler mechanism since protonation at the indole-2 position was not rate determining as demonstrated by kinetic isotope effects. Based on this kinetic data, the retro-Pictet−Spengler pathway was ruled out for the cis to trans epimerization of 1,2,3-trisubstituted 1,2,3,4-tetrahydro-β-carbolines, while the olefinic mechanism had been ruled out by experiments carried out in TFA-d.
Rationale
The stress-induced hyperthermia (SIH) model is an anxiety model that uses the transient rise in body temperature in response to acute stress. Benzodiazepines produce anxiolytic as well as ...sedative side effects through nonselective binding to GABA
A
receptor subunits. The GABA
A
receptor α
1
subunit is associated with sedation, whereas the GABA
A
receptor α
2
and α
3
subunits are involved in anxiolytic effects.
Objectives
We therefore examined the effects of (non)subunit-selective GABA
A
receptor agonists on temperature and locomotor responses to novel cage stress.
Results
Using telemetric monitoring of temperature and locomotor activity, we found that nonsubunit-selective GABA
A
receptor agonist diazepam as well as the α
3
subunit-selective receptor agonist TP003 dose-dependently attenuated SIH and locomotor responses. Administration of GABA
A
receptor α
1
-selective agonist zolpidem resulted in profound hypothermia and locomotor sedation. The GABA
A
receptor α
1
-selective antagonist βCCt antagonized the hypothermia, but did not reverse the SIH response attenuation caused by diazepam and zolpidem. These results suggest an important regulating role for the α
1
subunit in thermoregulation and sedation. Ligands of extrasynaptic GABA
A
receptors such as alcohol and nonbenzodiazepine THIP attenuated the SIH response only at high doses.
Conclusions
The present study confirms a putative role for the GABA
A
receptor α
1
subunit in hypothermia and sedation and supports a role for α
2/3
subunit GABA
A
receptor agonists in anxiety processes. In conclusion, we show that home cage temperature and locomotor responses to novel home cage stress provide an excellent tool to assess both anxiolytic and sedative effects of various (subunit-selective) GABA
A
ergic compounds.
Rationale
Assays of schedule-controlled responding can be used to characterize the pharmacology of benzodiazepines and other GABA
A
receptor modulators, and are sensitive to changes in drug effects ...that are related to physical dependence.
Objective
The present study used this approach to investigate the role of GABA
A
receptor subtypes in mediating dependence-like effects following benzodiazepine administration.
Methods
Squirrel monkeys (
n
= 6) were trained on a fixed-ratio schedule of food reinforcement. Initially, the response rate-decreasing effects of chlordiazepoxide (0.1–10 mg/kg; nonselective GABA
A
receptor agonist), zolpidem (0.032–1.0 mg/kg; α1 subunit-containing GABA
A
subtype-preferring agonist), and HZ-166 (0.1–10 mg/kg; functionally selective α2 and α3 subunit-containing GABA
A
receptor agonist) were assessed. Next, acute dependence-like effects following single injections of chlordiazepoxide, zolpidem, and HZ-166 were assessed with flumazenil (0.1–3.2 mg/kg; nonselective GABA
A
receptor antagonist). Finally, acute dependence-like effects following zolpidem administration were assessed with βCCt and 3-PBC (0.1–3.2 mg/kg and 0.32–10 mg/kg, respectively; α1 subunit-containing GABA
A
receptor antagonists).
Results
Chlordiazepoxide, zolpidem, and HZ-166 produced dose- and time-dependent decreases in response rates, whereas flumazenil, βCCT, and 3-PBC were ineffective. After the drug effects waned, flumazenil produced dose-dependent decreases in response rates following administration of 10 mg/kg chlordiazepoxide and 1.0 mg/kg zolpidem, but not following any dose of HZ-166. Further, both βCCT and 3-PBC produced dose-dependent decreases in response rates when administered after 1.0 mg/kg zolpidem.
Conclusions
These data raise the possibility that α1 subunit-containing GABA
A
receptors play a major role in physical dependence-related behaviors following a single injection of a benzodiazepine.
Rationale
The various α subtypes of GABA
A
receptors have been strongly implicated in alcohol reinforcement and consumption.
Objectives
The effects of the GABA
A
α1-preferring ligand, ...3-propoxy-β-carboline hydrochloride (3-PBC), on seeking and self-administration responses were evaluated in two groups of baboons trained under a 3-component chained schedule of reinforcement (CSR).
Methods
Alcohol (4 % w/v;
n
= 5; alcohol group) or a preferred nonalcoholic beverage (
n
= 4; control group) was available for self-administration only in component 3 of the CSR. Responses in component 2 provided indices of motivation to drink (seeking). 3-PBC (1.0–30.0 mg/kg) and saline were administered before drinking sessions under both acute and 5-day dosing conditions.
Results
Repeated, and not acute, doses of 3-PBC significantly decreased total self-administration responses (
p
< 0.05), volume consumed (
p
< 0.05), and gram per kilogram of alcohol (
p
< 0.05) in the alcohol group. In the control group, 5-day administration of 3-PBC significantly decreased total self-administration responses (
p
< 0.05) but produced nonsignificant decreases in volume consumed. Within-session pattern of drinking was characterized by a high level of drinking in the first 20 min of the session for both groups, which was significantly (
p
< 0.05) decreased by all doses of 3-PBC (1.0–18.0 mg/kg) only in the alcohol group. In contrast, the first drinking bout in the control group was only reduced at the highest doses of 3-PBC (10.0 and 18.0 mg/kg).
Conclusions
The results support the involvement of the GABA
A
α1 subtype receptor in alcohol reinforcement and consumption.
Benzodiazepines negatively affect motor coordination and balance and produce myorelaxation. The aim of the present study was to examine the extent to which populations of γ-aminobutyric acid A ...(GABAA) receptors containing α1 and α5 subunits contribute to these motor-impairing effects in rats. We used the nonselective agonist diazepam and the α1-selective agonist zolpidem, as well as nonselective, α1-subunit and α5-subunit-selective antagonists flumazenil, βCCt, and XLi093, respectively. Ataxia and muscle relaxation were assessed by rotarod and grip strength tests performed 20 min after intraperitoneal treatment. Diazepam (2 mg/kg) induced significant ataxia and muscle relaxation, which were completely prevented by pretreatment with flumazenil (10 mg/kg) and βCCt (20 mg/kg). XLi093 antagonized the myorelaxant, but not the ataxic actions of diazepam. All three doses of zolpidem (1, 2, and 5 mg/kg) produced ataxia, but only the highest dose (5 mg/kg) significantly decreased the grip strength. These effects of zolpidem were reversed by βCCt at doses of 5 and 10 mg/kg, respectively. The present study demonstrates that α1 GABAA receptors mediate ataxia and indirectly contribute to myorelaxation in rats, whereas α5 GABAA receptors contribute significantly, although not dominantly, to muscle relaxation but not ataxia.
Synaptic plasticity in the amydgala is essential for emotional learning. Fear conditioning, for example, depends on changes in excitatory transmission that occur following NMDA receptor activation ...and AMPA receptor modification in this region. The role of these and other glutamatergic mechanisms have been studied extensively in this circuit while relatively little is known about the contribution of inhibitory transmission. The current experiments addressed this issue by examining the role of the GABA(A) receptor subunit α1 in fear learning and plasticity. We first confirmed previous findings that the α1 subunit is highly expressed in the lateral nucleus of the amygdala. Consistent with this observation, genetic deletion of this subunit selectively enhanced plasticity in the lateral amygdala and increased auditory fear conditioning. Mice with selective deletion of α1 in excitatory cells did not exhibit enhanced learning. Finally, infusion of a α1 receptor antagonist into the lateral amygdala selectively impaired auditory fear learning. Together, these results suggest that inhibitory transmission mediated by α1-containing GABA(A) receptors plays a critical role in amygdala plasticity and fear learning.
Abstract Despite significant advances in understanding the role of benzodiazepine (BZ)-sensitive populations of GABAA receptors, containing the α1 , α2 , α3 or α5 subunit, factual substrates of ...BZ-induced learning and memory deficits are not yet fully elucidated. It was shown that α1 -subunit affinity-selective antagonist β -CCt almost completely abolished spatial learning deficits induced by diazepam (DZP) in the Morris water maze. We examined a novel, highly (105 fold) α1 -subunit selective ligand—WYS8 (0.2, 1 and 10 mg/kg), on its own and in combination with the non-selective agonist DZP (2 mg/kg) or β -CCt (5 mg/kg) in the water maze in rats. The in vitro efficacy study revealed that WYS8 acts as α1 -subtype selective weak partial positive modulator (40% potentiation at 100 nM). Measurement of concentrations of WYS8 and DZP in rat serum and brain tissues suggested that they did not substantially cross-influence the respective disposition. In the water maze, DZP impaired spatial learning (acquisition trials) and memory (probe trial). WYS8 caused no effect per se , did not affect the overall influence of DZP on the water-maze performance and was devoid of any activity in this task when combined with β -CCt. Nonetheless, an additional analysis of the latency to reach the platform and the total distance swam suggested that WYS8 addition attenuated the run-down of the spatial impairment induced by DZP at the end of acquisition trials. These results demonstrate a clear difference in the influence of an α1 subtype-selective antagonist and a partial agonist on the effects of DZP on the water-maze acquisition.
To gain access to 3-propoxy-β-carboline hydrochloride (3-PBC·HCl) (1·HCl) and β-carboline-3-carboxylate-tert-butyl ester (βCCt) (2), potential clinical agents active against alcohol ...self-administration, a two-step route was developed. This process involves a palladium-catalyzed Buchwald–Hartwig coupling and an intramolecular Heck reaction. This two-step route provides rapid access to multigram quantities of 3-PBC (1) and βCCt (2), as well as analogues for studies of alcohol self-administration. The overall yield of 3-PBC (1) was improved from 8% to 50% by this route.
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