Smith CP

References (5)

Title : Activation of cholinergic receptors blocks non-adrenergic non-cholinergic contractions in the rat urinary bladder - Lai_2008_Brain.Res.Bull_77_420
Author(s) : Lai HH , Smith CP , Munoz A , Boone TB , Szigeti GP , Somogyi GT
Ref : Brain Research Bulletin , 77 :420 , 2008
Abstract : In the present study, the plasticity of the non-adrenergic non-cholinergic (NANC) response was investigated. Isolated rat bladder strips were electrically stimulated and the evoked contractions were isometrically recorded. The NANC part of the contractions were unmasked by applying 500 nM 4-DAMP, a potent muscarinic antagonist. Treatment of the bladder strips with 10 microM carbachol (a cholinergic agonist) increased the muscle tone but did not alter the neurally evoked contractions. However, carbachol decreased: (1) the NANC response from 74.6% to 33.3% of control and (2) the purinergic contractile response to alpha,beta-methylene ATP (alpha,beta-mATP) (10 microM) from 97.0% to 43.4% (p<0.05). Treatment with the cholinesterase inhibitor eserine (10 microM) also significantly decreased the NANC response to 21.1% (p<0.0001). The purinergic receptor antagonist suramin (100 microM) did not affect the neurally evoked contractions, however; subsequent addition of 4-DAMP decreased the contractions to 31%. Activation of the smooth muscle cholinergic receptors (with carbachol or eserine) and purinergic receptors (with alpha,beta-mATP) decreased the NANC contractions and the direct contractile response to alpha,beta-mATP. When the electrically evoked contractions were facilitated by the L-type Ca2+ channel activator, Bay-K 8644 the subsequent application of 4-DAMP did not unmask inhibited NANC contractions. We conclude that activation of muscarinic receptors by cholinergic agonist, carbachol or by endogenous acetylcholine (ACh) induce a cascade of events that leads to diminished purinergic response and consequently an inhibition of the bladder NANC response.
ESTHER : Lai_2008_Brain.Res.Bull_77_420
PubMedSearch : Lai_2008_Brain.Res.Bull_77_420
PubMedID: 18755252

Title : Pharmacological activity and safety profile of P10358, a novel, orally active acetylcholinesterase inhibitor for Alzheimer's disease - Smith_1997_J.Pharmacol.Exp.Ther_280_710
Author(s) : Smith CP , Bores GM , Petko W , Li M , Selk DE , Rush DK , Camacho F , Winslow JT , Fishkin R , Cunningham DM , Brooks KM , Roehr J , Hartman HB , Davis L , Vargas HM
Ref : Journal of Pharmacology & Experimental Therapeutics , 280 :710 , 1997
Abstract : 1-[(3-Fluoro-4-pyridinyl)amino]-3-methyl-1(H)-indol-5-yl methyl carbamate (P10358) is a potent, reversible acetylcholinesterase inhibitor that produces central cholinergic stimulation after oral and parental administration in rats and mice. P10358 is a 2.5 times more potent acetylcholinesterase inhibitor than THA in vitro (IC50 = 0.10 +/- 0.02 microM vs. IC50 = 0.25 +/- 0.03 microM). It also inhibits butyrylcholinesterase activity as potently as THA (IC50 = 0.08 +/- 0.05 microM vs. IC50 = 0.07 +/- 0.01 microM). Ex vivo, P10358 (0.2 - 20 mg/kg, p.o.) produced dose-dependent inhibition of brain acetylcholinesterase activity. At 10 and 20 mg/ kg, it produced profound and long-lasting hypothermia in mice. P10358 enhanced performance in rats in a step-down passive avoidance task (0.62 and 1.25 mg/kg) and in a social recognition paradigm (0.32, 0.64 and 1.25 mg/kg) in mice. It reversed scopolamine-induced deficits in the Morris Water maze in rats (1.25 and 2.5 mg/kg) and a higher dose elevated striatal homovanillic acid levels. These behavioral and biochemical effects are consistent with central cholinergic stimulation. Hemodynamic studies in the rat demonstrated a 16-fold separation between behaviorally active doses (1.25 mg/kg) and those that elevated arterial pressure (20 mg/kg). Lethality in rats occurred at an oral dose of 80 mg/kg, but not at lower doses. Chemically, P10358 is an N-aminoindole and may not have the hepatotoxic liability associated with aminoacridine structure of tacrine. P10358 had weak affinity (>10 microM) at a variety of aminergic and peptidergic receptors and uptake carriers. These properties suggest that P10358 may be a safe and promising symptomatic treatment for Alzheimer's disease.
ESTHER : Smith_1997_J.Pharmacol.Exp.Ther_280_710
PubMedSearch : Smith_1997_J.Pharmacol.Exp.Ther_280_710
PubMedID: 9023283

Title : Alpha 2-adrenoceptor antagonists potentiate acetylcholinesterase inhibitor effects on passive avoidance learning in the rat - Camacho_1996_Psychopharmacology_124_347
Author(s) : Camacho F , Smith CP , Vargas HM , Winslow JT
Ref : Psychopharmacology , 124 :347 , 1996
Abstract : The cholinergic hypothesis of Alzheimer's disease (AD) has strongly influenced research on learning and memory over the last decade. However, there has been limited success treating AD dementia with cholinomimetics. Furthermore, there are indications that other neurotransmitter systems affected by this disease may be involved in cognitive processes. Animal studies have suggested that norepinephrine and acetylcholine may interact in learning and memory. The current experiments investigate this interaction in a step-down passive avoidance paradigm after coadministration of acetylcholinesterase inhibitors and alpha 2-adrenoceptor antagonists. Administration of acetylcholinesterase inhibitors heptylphysostigmine (0.625-5.0 mg/kg, IP), tacrine (2.5-10.0 mg/kg, PO), velnacrine (0.312-2.5 mg/kg, SC), and galanthamine (0.312-2.5 mg/kg IP) each enhanced retention of a passive avoidance response at selected moderate doses administered 30-60 min prior to training. The alpha 2-adrenoceptor antagonists idazoxan (0.312-2.5 mg/kg, IP), yohimbine (0.078-0.312 mg/kg, IP) and P86 7480 (0.156-0.625 mg/kg, IP) alone failed to enhance learning in this paradigm. Coadministration of a subthreshold dose of heptylphysostigmine (0.625 mg/kg, IP) with doses of idazoxan, yohimbine or P86 7480 enhanced passive avoidance learning. This synergistic interaction may represent effects of antagonism of presynaptic alpha 2-adrenoceptor since coadministration of heptylphysostigmine and the selective postsynaptic alpha 2-adrenoceptor antagonist SKF 104856 did not result in enhanced learning. Taken together these data suggest noradrenergic activation through pre-synaptic alpha 2-adrenoceptor blockade may potentiate cholinergic activity in the formation of a long-term memory trace. These observations may have implications for the treatment of AD with cholinergic and adrenergic agents.
ESTHER : Camacho_1996_Psychopharmacology_124_347
PubMedSearch : Camacho_1996_Psychopharmacology_124_347
PubMedID: 8739550

Title : Aminopyridine carbamic acid esters: synthesis and potential as acetylcholinesterase inhibitors and acetylcholine releasers - Shutske_1992_J.Pharm.Sci_81_380
Author(s) : Shutske GM , Tomer JD , Kapples KJ , Hrib NJ , Jurcak JG , Bores GM , Huger FP , Petko W , Smith CP
Ref : J Pharm Sci , 81 :380 , 1992
Abstract : 4-Amino-3-pyridyl carbamates (2a-c) were synthesized as potential acetylcholinesterase inhibitors and acetylcholine releasers on the basis of the reported activity of the analogous N-(4-amino-3-pyridyl)-N',N'-dimethylurea (1). Although 4-amino-3-pyridyl N,N-dimethylcarbamate (2b) showed good cholinesterase inhibition [concentration that elicited a 50% reduction in the maximal enzyme response (IC50) was 13.4 microM], it had no effect on the stimulated release of [3H]acetylcholine from rat striatal slices. 4-[[(Dimethylamino)methylene]amino]-3-pyridyl N,N-dimethylcarbamate (7a), an intermediate in the synthesis of 2b, demonstrated surprisingly good cholinesterase inhibition (IC50 was 9.4 microM) but showed no activity as a release. A precursor to 7a, N-(3-hydroxy-4-pyridyl)-N',N'-dimethylformamidine (6a), showed some activity in release but was not an esterase inhibitor, whereas the precursor to 6a, 4-amino-3-pyridinol (5a), was a potent releaser. A new synthesis of 5a, based on an ortho-directed lithiation strategy, is also reported.
ESTHER : Shutske_1992_J.Pharm.Sci_81_380
PubMedSearch : Shutske_1992_J.Pharm.Sci_81_380
PubMedID: 1501077

Title : A comparison of solubilized and membrane bound forms of choline-O-acetyltransferase (EC 2.3.1.6) in mouse brain nerve endings -
Author(s) : Smith CP , Carroll PT
Ref : Brain Research , 185 :363 , 1980
PubMedID: 7357434