12 research outputs found
Scale-Up of Microwave-Promoted Reactions to the Multigram Level Using a Sealed-Vessel Microwave Apparatus
A range of synthetic transformations have been scaled up successfully using a sealed-vessel multimode microwave unit. These include metal-catalyzed couplings, synthesis of heterocycles, reactions under an atmosphere of reactive gas and two-step one-pot procedures. Also, observations have been made along the way that are of use to chemists addressing scale-up of microwave-promoted reactions
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Design, synthesis and biological evaluation of a bi-specific vaccine against α-pyrrolidinovalerophenone (α-PVP) and 3,4-methylenedioxypyrovalerone (MDPV) in rats
•An α-PVP/MDPV hapten was conjugated to an antigen to make a vaccine for both α-PVP and MDPV.•The α-PVP/MDPV vaccine produced racemic α-PVP and MDPV antibodies in male rats.•The α-PVP/MDPV vaccine reduced hyperlocomotion and organ drug concentrations.•The vaccine shortened the duration of activity up to 5.6 mg/kg of α-PVP or MDPV.
α-PVP (α-pyrrolidinovalerophenone) and MDPV (3,4-methylenedioxypyrovalerone) are potent abused stimulants that are members of the synthetic cathinone class of drugs. Although these drugs are taken with recreational intent, high doses can lead to unintended adverse effects including agitation, cardiovascular effects, sympathomimetic syndromes, hallucinations, and psychoses. One possible treatment is the use of a vaccine to block or attenuate adverse medical effects. These studies report the preparation of a vaccine that generates high affinity antibodies specific for both drugs and the pharmacological testing of this vaccine in male rats. Alkylation of a hydroxy-α-PVP analog with an appropriate thiol-bearing linker afforded the hapten. When hapten-conjugated carrier protein was mixed with adjuvant, the resulting vaccine stimulated production of antibodies in male Sprague Dawley rats that were found to significantly reduce α-PVP- and MDPV-induced hyperlocomotion as well as to significantly reduce the concentrations of MDPV drugs in critical organs. The novel vaccine produced high affinity antibodies against MDPV, (R)-MDPV, (S)-MDPV, and α-PVP. Cross-reactivity testing against nine structurally similar cathinones showed very limited binding, and no binding to off-target endogenous and exogenous compounds. Antibodies generated by this bi-specific vaccine also significantly shortened the duration of locomotor activity induced by both drugs up to a dose of 5.6 mg/kg in male rats
Design, Synthesis, and Biological Evaluation of Structurally Rigid Analogues of 4‑(3-Hydroxyphenyl)piperidine Opioid Receptor Antagonists
In order to gain additional information
concerning the active conformation
of the <i>N</i>-substituted <i>trans</i>-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine
(<b>1</b>) class of opioid receptor antagonists, procedures
were developed for the synthesis of structurally rigid <i>N</i>-substituted-6-(3-hydroxyphenyl)3-azabicyclo[3.1.0]hexane
and 3-methyl-4-(3-hydroxyphenyl)-4-azabicyclo[4.1.0]heptanes.
Evaluation of the conformationally constrained series in a [<sup>35</sup>S]GTPγS assay showed that structural rigid compounds having
the 3-hydroxyphenyl group locked in the piperidine equatorial orientation
had potencies equal to or better than similar compounds having more
flexible structures similar to <b>1</b>. The studies of the
rigid compounds also suggested that the 3-methyl group present in
compound <b>1</b> type antagonists may not be necessary for
their pure opioid antagonist properties
Discovery of <i>N</i>‑{4-[(3-Hydroxyphenyl)-3-methylpiperazin-1-yl]methyl-2-methylpropyl}-4-phenoxybenzamide Analogues as Selective Kappa Opioid Receptor Antagonists
There is continuing interest in the
discovery and development of
new κ opioid receptor antagonists. We recently reported that
N-substituted 3-methyl-4-(3-hydroxyphenyl)piperazines were a new class
of opioid receptor antagonists. In this study, we report the syntheses
of two piperazine JDTic-like analogues. Evaluation of the two compounds
in an in vitro [<sup>35</sup>S]GTPγS binding assay showed that
neither compound showed the high potency and κ opioid receptor
selectivity of JDTic. A library of compounds using the core scaffold <b>21</b> was synthesized and tested for their ability to inhibit
[<sup>35</sup>S]GTPγS binding stimulated by the selective κ
opioid agonist U69,593. These studies led to <i>N</i>-[(1<i>S</i>)-1-{[(3<i>S</i>)-4-(3-hydroxyphenyl)-3-methylpiperazin-1-yl]methyl}-2-methylpropyl]-4-phenoxybenzamide
(<b>11a</b>), a compound that showed good κ opioid receptor
antagonist properties. An SAR study based on <b>11a</b> provided
28 novel analogues. Evaluation of these 28 compounds in the [<sup>35</sup>S]GTPγS binding assay showed that several of the analogues
were potent and selective κ opioid receptor antagonists