McHardy Smith | Lecom - Academia.edu (original) (raw)
Papers by McHardy Smith
Bioorganic & Medicinal Chemistry Letters, 2007
A series of benzazepinones were synthesized and evaluated as hNa v 1.7 sodium channel blockers. S... more A series of benzazepinones were synthesized and evaluated as hNa v 1.7 sodium channel blockers. Several compounds from this series displayed good oral bioavailability and exposure and were efficacious in a rat model of neuropathic pain.
Bioorganic & Medicinal Chemistry Letters, 2013
A series of benzazepinones were synthesized and evaluated for block of Na v 1.7 sodium channels. ... more A series of benzazepinones were synthesized and evaluated for block of Na v 1.7 sodium channels. Compound 30 from this series displayed potent channel block, good selectivity versus other targets, and dose-dependent oral efficacy in a rat model of neuropathic pain.
Bioorganic & Medicinal Chemistry Letters, 2010
Voltage-gated sodium channels have been shown to play a critical role in neuropathic pain. A seri... more Voltage-gated sodium channels have been shown to play a critical role in neuropathic pain. A series of low molecular weight biaryl substituted pyrazole carboxamides were identified with good in-vitro potency and in-vivo efficacy. Compound 26, a Na v 1.7 blocker has excellent efficacy in the Chung model of neuropathic pain.
Bioorganic & Medicinal Chemistry Letters, 2010
A series of novel biphenyl pyrazole dicarboxamides were identified as potential sodium channel bl... more A series of novel biphenyl pyrazole dicarboxamides were identified as potential sodium channel blockers for treatment of neuropathic pain. Compound 20 had outstanding efficacy in the Chung rat spinal nerve ligation (SNL) model of neuropathic pain.
Journal of Biological Chemistry
During the process by which newly synthesized subunits of the nicotinic acetylcholine receptor (s... more During the process by which newly synthesized subunits of the nicotinic acetylcholine receptor (stoichiometry = alpha 2 beta gamma delta) mature and acquire the properties of the fully functional cell surface receptor, they undergo numerous covalent and noncovalent modifications. Using ligand-mediated and subunit-specific immunoprecipitation, four forms in the maturation of the alpha subunit can be detected: the primary translation product; alpha subunit that can bind alpha-bungarotoxin; alpha subunit assembled with the other subunits; and surface receptor. The alpha subunit acquires the ability to bind alpha-bungarotoxin with a t1/2 of approximately 40 min after translation and becomes assembled with a t1/2 of 80 min after translation. Using metabolic labeling and sucrose gradient fractionation, we have determined the subcellular location of alpha subunit when it acquires the ability to bind alpha-bungarotoxin and when it is assembled. Golgi membranes were identified across the gra...
The American journal of physiology, 1995
Using Ca2+ channel blockers with different specificities for L- and T-type Ca2+ channels, we have... more Using Ca2+ channel blockers with different specificities for L- and T-type Ca2+ channels, we have investigated the roles of these two channel types in K(+)-induced aldosterone secretion. In whole cell voltage-clamp experiments, the spider toxin omega-agatoxin-IIIA (omega-Aga-IIIA) completely blocks L-type Ca2+ channels but has no effect on T-type Ca2+ channels. In contrast, Ni2+ and 1,4-dihydropyridines block both L- and T-type Ca2+ channels. Secretion induced by 7 mM extracellular K+ concentration ([K+]o) is unaffected by omega-Aga-IIIA but is strongly inhibited by Ni2+ or the 1,4-dihydropyridine, nitrendipine. This suggests that physiological increases in [K+]o stimulate aldosterone secretion primarily by enhancing Ca2+ entry through T-type Ca2+ channels. Surprisingly, secretion induced by 60 mM [K+]o is enhanced by omega-Aga-IIIA or Ni2+ and is inhibited by the L-type Ca2+ channel activator BAY K 8644. Nitrendipine (1 nM) also stimulates such secretion, although higher concentrat...
Journal of cyclic nucleotide and protein phosphorylation research, 1985
The regulation of adenylate cyclase by muscarinic cholinergic receptors has been studied in rat h... more The regulation of adenylate cyclase by muscarinic cholinergic receptors has been studied in rat heart membranes. In the presence of isoproterenol the K0.5 for Mg2+-mediated activation of adenylate cyclase was 0.1 mM; the addition of the muscarinic receptor agonist oxotremorine increased the K0.5 for Mg2+, and activation by Mg2+ no longer followed mass action kinetics for a single site interaction. The extent of oxotremorine-mediated attenuation of adenylate cyclase exhibited a Mg2+ concentration dependence: in short-time assays at 0.25 mM free Mg2+ the attenuation of enzyme activity was 55 percent, whereas at 20mM Mg2+, only 20 percent inhibition was observed. The increase in the apparent K0.5 for Mg2+ in the presence of oxotremorine was less in 20 min assays than in 4 min assays. The effects of oxotremorine on the rates of activation and deactivation of adenylate cyclase also were examined. Oxotremorine increased the rate of deactivation of adenylate cyclase by two-fold. At low fre...
Advances in cyclic nucleotide and protein phosphorylation research, 1985
The occurrence of muscarinic cholinergic receptor-mediated activation of phosphodiesterase in 132... more The occurrence of muscarinic cholinergic receptor-mediated activation of phosphodiesterase in 1321N1 cells does not represent an isolated phenomenon, since a similar response to cholinergic stimuli is observed in thyroid slices (45) and WI-38 fibroblasts (1,42). Both muscarinic-receptor-mediated inhibition of adenylate cyclase and activation of phosphodiesterase occur in WI-38 fibroblasts (42). Work currently under way in our laboratory is directed toward determining if a guanine nucleotide regulatory protein is involved in the activation of phosphodiesterase in these cells and whether common or separate populations of muscarinic receptors are coupled to these two mechanisms of cyclic AMP metabolism. The analysis of acute hormonal regulation of phosphodiesterase in intact cells is sufficiently complicated to have previously discouraged investigators from pursuing this question in mammalian tissues. The 1321N1 cell line provides a simple model system in which at least one mechanism o...
Molecular pharmacology, 1992
The peptide omega-agatoxin IIIA (omega-Aga-IIIA) from venom of the funnel web spider Agelenopsis ... more The peptide omega-agatoxin IIIA (omega-Aga-IIIA) from venom of the funnel web spider Agelenopsis aperta blocks L-type Ca2+ channels in neurons and myocardial cells with high affinity. We report that omega-Aga-IIIA also blocks whole-cell Ca2+ channel currents in guinea pig atrial myocytes. Although other high affinity blockers of L-type Ca2+ channels are available (such as the 1,4-dihydropyridines), omega-Aga-IIIA is a valuable pharmacological tool; omega-Aga-IIIA is the only known ligand that blocks L-type Ca2+ channels with high affinity at all voltages (IC50 approximately 1 nM) and it causes little or no block of T-type Ca2+ channels, unlike the 1,4-dihydropyridines. We use omega-Aga-IIIA to selectively eliminate L-type Ca2+ currents and we show that felodipine blocks T-type Ca2+ currents. Consequently, the toxin is better than dihydropyridines for separating ionic currents through voltage-dependent Ca2+ channels and defining their physiological function.
Journal of Medicinal Chemistry, 2012
The voltage-gated calcium channel Ca(v)2.2 (N-type calcium channel) is a critical regulator of sy... more The voltage-gated calcium channel Ca(v)2.2 (N-type calcium channel) is a critical regulator of synaptic transmission and has emerged as an attractive target for the treatment of chronic pain. We report here the discovery of sulfonamide-derived, state-dependent inhibitors of Ca(v)2.2. In particular, 19 is an inhibitor of Ca(v)2.2 that is selective over cardiac ion channels, with a good preclinical PK and biodistribution profile. This compound exhibits dose-dependent efficacy in preclinical models of inflammatory hyperalgesia and neuropathic allodynia and is devoid of ancillary cardiovascular or CNS pharmacology at the doses tested. Importantly, 19 exhibited no efficacy in Ca(v)2.2 gene-deleted mice. The discovery of metabolite 26 confounds further development of members of this aminopiperidine sulfonamide series. This discovery also suggests specific structural liabilities of this class of compounds that must be addressed.
Bioorganic & Medicinal Chemistry Letters, 2013
A series of benzazepinones were synthesized and evaluated for block of Na v 1.7 sodium channels. ... more A series of benzazepinones were synthesized and evaluated for block of Na v 1.7 sodium channels. Compound 30 from this series displayed potent channel block, good selectivity versus other targets, and dose-dependent oral efficacy in a rat model of neuropathic pain.
Biological Control, 1997
Bioorganic & Medicinal Chemistry Letters, 2007
A series of benzazepinones were synthesized and evaluated as hNa v 1.7 sodium channel blockers. S... more A series of benzazepinones were synthesized and evaluated as hNa v 1.7 sodium channel blockers. Several compounds from this series displayed good oral bioavailability and exposure and were efficacious in a rat model of neuropathic pain.
Bioorganic & Medicinal Chemistry Letters, 2013
A series of benzazepinones were synthesized and evaluated for block of Na v 1.7 sodium channels. ... more A series of benzazepinones were synthesized and evaluated for block of Na v 1.7 sodium channels. Compound 30 from this series displayed potent channel block, good selectivity versus other targets, and dose-dependent oral efficacy in a rat model of neuropathic pain.
Bioorganic & Medicinal Chemistry Letters, 2010
Voltage-gated sodium channels have been shown to play a critical role in neuropathic pain. A seri... more Voltage-gated sodium channels have been shown to play a critical role in neuropathic pain. A series of low molecular weight biaryl substituted pyrazole carboxamides were identified with good in-vitro potency and in-vivo efficacy. Compound 26, a Na v 1.7 blocker has excellent efficacy in the Chung model of neuropathic pain.
Bioorganic & Medicinal Chemistry Letters, 2010
A series of novel biphenyl pyrazole dicarboxamides were identified as potential sodium channel bl... more A series of novel biphenyl pyrazole dicarboxamides were identified as potential sodium channel blockers for treatment of neuropathic pain. Compound 20 had outstanding efficacy in the Chung rat spinal nerve ligation (SNL) model of neuropathic pain.
Journal of Biological Chemistry
During the process by which newly synthesized subunits of the nicotinic acetylcholine receptor (s... more During the process by which newly synthesized subunits of the nicotinic acetylcholine receptor (stoichiometry = alpha 2 beta gamma delta) mature and acquire the properties of the fully functional cell surface receptor, they undergo numerous covalent and noncovalent modifications. Using ligand-mediated and subunit-specific immunoprecipitation, four forms in the maturation of the alpha subunit can be detected: the primary translation product; alpha subunit that can bind alpha-bungarotoxin; alpha subunit assembled with the other subunits; and surface receptor. The alpha subunit acquires the ability to bind alpha-bungarotoxin with a t1/2 of approximately 40 min after translation and becomes assembled with a t1/2 of 80 min after translation. Using metabolic labeling and sucrose gradient fractionation, we have determined the subcellular location of alpha subunit when it acquires the ability to bind alpha-bungarotoxin and when it is assembled. Golgi membranes were identified across the gra...
The American journal of physiology, 1995
Using Ca2+ channel blockers with different specificities for L- and T-type Ca2+ channels, we have... more Using Ca2+ channel blockers with different specificities for L- and T-type Ca2+ channels, we have investigated the roles of these two channel types in K(+)-induced aldosterone secretion. In whole cell voltage-clamp experiments, the spider toxin omega-agatoxin-IIIA (omega-Aga-IIIA) completely blocks L-type Ca2+ channels but has no effect on T-type Ca2+ channels. In contrast, Ni2+ and 1,4-dihydropyridines block both L- and T-type Ca2+ channels. Secretion induced by 7 mM extracellular K+ concentration ([K+]o) is unaffected by omega-Aga-IIIA but is strongly inhibited by Ni2+ or the 1,4-dihydropyridine, nitrendipine. This suggests that physiological increases in [K+]o stimulate aldosterone secretion primarily by enhancing Ca2+ entry through T-type Ca2+ channels. Surprisingly, secretion induced by 60 mM [K+]o is enhanced by omega-Aga-IIIA or Ni2+ and is inhibited by the L-type Ca2+ channel activator BAY K 8644. Nitrendipine (1 nM) also stimulates such secretion, although higher concentrat...
Journal of cyclic nucleotide and protein phosphorylation research, 1985
The regulation of adenylate cyclase by muscarinic cholinergic receptors has been studied in rat h... more The regulation of adenylate cyclase by muscarinic cholinergic receptors has been studied in rat heart membranes. In the presence of isoproterenol the K0.5 for Mg2+-mediated activation of adenylate cyclase was 0.1 mM; the addition of the muscarinic receptor agonist oxotremorine increased the K0.5 for Mg2+, and activation by Mg2+ no longer followed mass action kinetics for a single site interaction. The extent of oxotremorine-mediated attenuation of adenylate cyclase exhibited a Mg2+ concentration dependence: in short-time assays at 0.25 mM free Mg2+ the attenuation of enzyme activity was 55 percent, whereas at 20mM Mg2+, only 20 percent inhibition was observed. The increase in the apparent K0.5 for Mg2+ in the presence of oxotremorine was less in 20 min assays than in 4 min assays. The effects of oxotremorine on the rates of activation and deactivation of adenylate cyclase also were examined. Oxotremorine increased the rate of deactivation of adenylate cyclase by two-fold. At low fre...
Advances in cyclic nucleotide and protein phosphorylation research, 1985
The occurrence of muscarinic cholinergic receptor-mediated activation of phosphodiesterase in 132... more The occurrence of muscarinic cholinergic receptor-mediated activation of phosphodiesterase in 1321N1 cells does not represent an isolated phenomenon, since a similar response to cholinergic stimuli is observed in thyroid slices (45) and WI-38 fibroblasts (1,42). Both muscarinic-receptor-mediated inhibition of adenylate cyclase and activation of phosphodiesterase occur in WI-38 fibroblasts (42). Work currently under way in our laboratory is directed toward determining if a guanine nucleotide regulatory protein is involved in the activation of phosphodiesterase in these cells and whether common or separate populations of muscarinic receptors are coupled to these two mechanisms of cyclic AMP metabolism. The analysis of acute hormonal regulation of phosphodiesterase in intact cells is sufficiently complicated to have previously discouraged investigators from pursuing this question in mammalian tissues. The 1321N1 cell line provides a simple model system in which at least one mechanism o...
Molecular pharmacology, 1992
The peptide omega-agatoxin IIIA (omega-Aga-IIIA) from venom of the funnel web spider Agelenopsis ... more The peptide omega-agatoxin IIIA (omega-Aga-IIIA) from venom of the funnel web spider Agelenopsis aperta blocks L-type Ca2+ channels in neurons and myocardial cells with high affinity. We report that omega-Aga-IIIA also blocks whole-cell Ca2+ channel currents in guinea pig atrial myocytes. Although other high affinity blockers of L-type Ca2+ channels are available (such as the 1,4-dihydropyridines), omega-Aga-IIIA is a valuable pharmacological tool; omega-Aga-IIIA is the only known ligand that blocks L-type Ca2+ channels with high affinity at all voltages (IC50 approximately 1 nM) and it causes little or no block of T-type Ca2+ channels, unlike the 1,4-dihydropyridines. We use omega-Aga-IIIA to selectively eliminate L-type Ca2+ currents and we show that felodipine blocks T-type Ca2+ currents. Consequently, the toxin is better than dihydropyridines for separating ionic currents through voltage-dependent Ca2+ channels and defining their physiological function.
Journal of Medicinal Chemistry, 2012
The voltage-gated calcium channel Ca(v)2.2 (N-type calcium channel) is a critical regulator of sy... more The voltage-gated calcium channel Ca(v)2.2 (N-type calcium channel) is a critical regulator of synaptic transmission and has emerged as an attractive target for the treatment of chronic pain. We report here the discovery of sulfonamide-derived, state-dependent inhibitors of Ca(v)2.2. In particular, 19 is an inhibitor of Ca(v)2.2 that is selective over cardiac ion channels, with a good preclinical PK and biodistribution profile. This compound exhibits dose-dependent efficacy in preclinical models of inflammatory hyperalgesia and neuropathic allodynia and is devoid of ancillary cardiovascular or CNS pharmacology at the doses tested. Importantly, 19 exhibited no efficacy in Ca(v)2.2 gene-deleted mice. The discovery of metabolite 26 confounds further development of members of this aminopiperidine sulfonamide series. This discovery also suggests specific structural liabilities of this class of compounds that must be addressed.
Bioorganic & Medicinal Chemistry Letters, 2013
A series of benzazepinones were synthesized and evaluated for block of Na v 1.7 sodium channels. ... more A series of benzazepinones were synthesized and evaluated for block of Na v 1.7 sodium channels. Compound 30 from this series displayed potent channel block, good selectivity versus other targets, and dose-dependent oral efficacy in a rat model of neuropathic pain.
Biological Control, 1997