The Journal of pharmacology and experimental therapeutics
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J. Pharmacol. Exp. Ther. · Dec 2001
Benzylidene analogs of anabaseine display partial agonist and antagonist properties at the mouse 5-hydroxytryptamine(3A) receptor.
The nicotinic receptor drug candidate, 3-(2,4-dimethoxybenzylidene)-anabaseine (also known as GTS-21; DMXBA), its hydroxy metabolites, and some related analogs were evaluated with the two-electrode voltage-clamp technique in mouse 5-hydroxytryptamine (5-HT)(3A) receptors expressed in Xenopus oocytes. Although DMXBA lacked partial agonist activity, its hydroxy-benzylidene metabolites and related analogs were partial agonists, displaying the following rank order of potency (EC(50)) and apparent efficacy: 5-HT, 0.9 +/- 0.06 microM (100% efficacy) > 3-(2-hydroxy,4-methoxybenzylidene)-anabaseine (2-OH-MBA), 2.0 +/- 0.3 microM (63% efficacy) > 3-(2,4-dihydroxybenzylidene)-anabaseine, 2.6 +/- 0.3 microM (63% efficacy) > 3-(2-methoxy,4-hydroxybenzylidene)-anabaseine, 17.2 +/- 1.0 microM (30% efficacy). To examine the influence of a benzylidene ring hydroxy substituent, the agonist actions of the three possible monohydroxy isomers were examined. ⋯ DMXBA demonstrated both competitive and noncompetitive forms of antagonism over the range of concentrations tested. These results suggest that a hydroxy substituent at the 2' position of the benzene ring is necessary and sufficient for partial agonist activity; substitution at the 4' position with a hydroxy or methoxy group further enhances agonist potency. Because 2-OH-MBA is a primary metabolite of DMXBA, it may contribute to the physiological, biochemical, and behavioral effects of the parent compound when administered in vivo.
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J. Pharmacol. Exp. Ther. · Dec 2001
Local anesthetics noncompetitively inhibit function of four distinct nicotinic acetylcholine receptor subtypes.
Local anesthetics (LAs) are considered to act primarily by inhibiting voltage-gated Na(+) channels. However, LAs also are pharmacologically active at other ion channels including nicotinic acetylcholine receptors (nAChR). nAChR exist as a family of diverse subtypes, each of which has a unique pharmacological profile. The current studies established effects of LAs on function of four human nAChR subtypes: naturally expressed muscle-type (alpha1*-nAChR) or autonomic (alpha3beta4*-nAChR) nAChR, or heterologously expressed nAChR containing alpha4 with either beta2- or beta4-subunits (alpha4beta2- or alpha4beta4-nAChR). ⋯ Its quaternary triethyl ammonium analog, QX-314, had greater inhibition potency, but the trimethyl ammonium derivative, QX-222, was the least potent LA at all but the alpha4beta2-nAChR subtype. With only a few exceptions, LA effects were consistent with noncompetitive inhibition of nAChR function and occurred at therapeutic doses. These studies suggest structural determinants for LA action at diverse nAChR subtypes and that nAChR likely are clinically relevant targets of LAs.
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J. Pharmacol. Exp. Ther. · Dec 2001
ReviewPharmacology of opioid and nonopioid analgesics in chronic pain states.
Chronic pain represents a mixture of pathophysiologic mechanisms, a complex assortment of spontaneous and elicited pain states, and a somewhat unpredictable response to analgesics. Opioids remain the mainstay of treatment of moderate to severe chronic pain, although there is little systematic examination to guide drug selection. Cyclooxygenase inhibitors play primarily an adjunctive role in chronic pain treatment. ⋯ A number of arthritic states have also been produced by means of chronic joint inflammation in rats. The pharmacology of these neuropathic and arthritic pain models generally resembles that found in the respective human conditions. Additional models of chronic pain, particularly visceral pain, have been developed; however, the pharmacology of these models is not well established at this time.