Background and Purpose The alpha 3 beta 4 subtype of nicotinic acetylcholine receptors (nAChRs) has been implicated in mediating nicotine reinforcement processes. AT-1001 has been recently described ...as a high-affinity and selective alpha 3 beta 4 nAChR antagonist that blocks nicotine self-administration in rats. The aim of this study was to investigate the mechanism of action underlying the nicotine-suppressive effects of AT-1001. Experimental Approach Effects of AT-1001 were determined using in vitro assays and rat models of nicotine addiction, and compared with varenicline. Key Results AT-1001 and its analogue AT-1012 were functionally selective as antagonists for alpha 3 beta 4 over alpha 4 beta 2 nAChRs, but not to the same extent as the binding selectivity, and had partial agonist activity at alpha 3 beta 4 nAChRs. In contrast, varenicline was a partial agonist at alpha 4 beta 2, a weak agonist at alpha 3 beta 4 and inhibited alpha 4 beta 2 at a much lower concentration than it inhibited alpha 3 beta 4 nAChRs. AT-1001 and varenicline also had very different in vivo properties. Firstly, AT-1001 did not exhibit reinforcing properties per se while varenicline was self-administered. Secondly, systemic treatment with AT-1001 did not induce reinstatement of nicotine seeking but rather attenuated reinstatement induced by varenicline, as well as nicotine. Finally, unlike varenicline, AT-1001 selectively blocked nicotine self-administration without altering alcohol lever pressing as assessed in an operant co-administration paradigm. Conclusions and Implications These findings describe a more complex AT-1001 in vitro profile than previously appreciated and provide further support for the potential of AT-1001 and congeners as clinically useful compounds for smoking cessation, with a mechanism of action distinct from currently available medications.
Nociceptin/Orphanin FQ (N/OFQ) regulates several biological functions via selective activation of the N/OFQ receptor (NOP). In this study novel nonpeptide NOP ligands were characterized in vitro in ...receptor binding and 35SGTPγS stimulated binding in membranes of cells expressing human NOP and classical opioid receptors, calcium mobilization assay in cells coexpressing the receptors and chimeric G proteins, bioluminescence resonance energy transfer (BRET) based assay for studying NOP receptor interaction with G protein and arrestin, the electrically stimulated mouse vas deferens and the mouse colon bioassays. The action of the AT compounds were compared with standard NOP agonists (N/OFQ and Ro 65–6570) and the NOP selective antagonist SB-612111. AT compounds displayed high NOP affinity and behaved as NOP agonists in all the functional assays consistently showing the following rank order of potency AT-127≥AT-090≥AT-035>AT-004= AT-001. AT compounds behaved as NOP full agonists in the calcium mobilization and mouse colon assays and as partial agonists in the 35SGTPγS and BRET assays. Interestingly AT-090 and AT-127, contrary to standard nonpeptide agonists that display G protein biased agonism, behaved as an unbiased agonists. AT-090 and AT-127 displayed higher NOP selectivity than Ro 65-6570 at native mouse receptors. AT-090 and AT-127 might be useful pharmacological tools for investigating the therapeutic potential of NOP partial agonists.
AT-090, a novel NOP-selective partial agonist.
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Background and Purpose The alpha3beta4 subtype of nicotinic acetylcholine receptors (nAChRs) has been implicated in mediating nicotine reinforcement processes. AT-1001 has been recently described as ...a high-affinity and selective alpha3beta4 nAChR antagonist that blocks nicotine self-administration in rats. The aim of this study was to investigate the mechanism of action underlying the nicotine-suppressive effects of AT-1001. Experimental Approach Effects of AT-1001 were determined using in vitro assays and rat models of nicotine addiction, and compared with varenicline. Key Results AT-1001 and its analogue AT-1012 were functionally selective as antagonists for alpha3beta4 over alpha4beta2 nAChRs, but not to the same extent as the binding selectivity, and had partial agonist activity at alpha3beta4 nAChRs. In contrast, varenicline was a partial agonist at alpha4beta2, a weak agonist at alpha3beta4 and inhibited alpha4beta2 at a much lower concentration than it inhibited alpha3beta4 nAChRs. AT-1001 and varenicline also had very different in vivo properties. Firstly, AT-1001 did not exhibit reinforcing properties per se while varenicline was self-administered. Secondly, systemic treatment with AT-1001 did not induce reinstatement of nicotine seeking but rather attenuated reinstatement induced by varenicline, as well as nicotine. Finally, unlike varenicline, AT-1001 selectively blocked nicotine self-administration without altering alcohol lever pressing as assessed in an operant co-administration paradigm. Conclusions and Implications These findings describe a more complex AT-1001 in vitro profile than previously appreciated and provide further support for the potential of AT-1001 and congeners as clinically useful compounds for smoking cessation, with a mechanism of action distinct from currently available medications.
New pyridone non-nucleoside reverse transcriptase inhibitors (NNRTIs) were prepared and several flexible routes to this class of inhibitor were identified. These NNRTIs were active inhibitors of the ...replication of wild-type and NNRTI-resistant HIV. Structure-based drug design was used to optimize the activity of the compounds against NNRTI-resistant mutants. The co-crystal structure of inhibitor
2b
in the NNRTI binding pocket of HIV reverse transcriptase (HIVRT) is also described.
New pyridone non-nucleoside reverse transcriptase inhibitors (NNRTIs) were prepared, and several flexible routes to this class of inhibitor were identified.
A series of 20 peptide analogs of (des-Glu1)conotoxin GI were prepared by solid phase synthesis. The peptides were tested for their abilities to inhibit contractions in the ...mouse-diaphragm-with-phrenic-nerve assay. (Des-Glu1)conotoxin has an IC50 of 2.7 x 10(-7) M in this assay. Results from this assay show that total loss of paralytic activity occurs when Pro is replaced by Gly, Tyr by D-Tyr, or Gly by D-Phe. In most cases loss or change in length of one of the disulfide rings eliminates paralytic activity except with compound 17, which is weakly active, IC50 = 7.0 x 10(-5) M. Replacement of the Cys1-Cys6 disulfide bond with an amide bond (compound 9) greatly lowers paralytic activity, IC50 = 3.7 x 10(-5) M.
THE SYNTHESIS OF 4"-DEOXYGENTAMICIN C1 MALLAMS, ALAN K.; VERNAY, H. FREDERICK; CROWE, DAVID F. ...
Journal of antibiotics,
01/1973, Letnik:
26, Številka:
12
Journal Article
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