PubMed Health⌕ Search

Biomedical subjects

L S Reynolds

Publications and source records attributed to L S Reynolds.

8 recordsLinked to original sources
PubMed1993

Pharmacology of CP-99,994; a nonpeptide antagonist of the tachykinin neurokinin-1 receptor.

(+)-(2S,3S)-3-(2-methoxybenzylamino)-2-phenylpiperidine (CP-99,994) binds selectively and with high affinity (Ki = 0.25 nM) to neurokinin (NK)-1 tachykinin receptors in a human cell line and in guinea pigs where it acts as an antagonist as evidenced by its blockade of substance P-induced excitation of locus coeruleus neurons in vitro. Subcutaneously administered CP-99,994 antagonized locomotor activity in guinea pigs induced by intraventricular infusion of [Sar9,Met(O2)11]-substance P (50 micrograms) with an ID50 = 0.59 mg/kg, indicating that CP-99,994 penetrates into the central nervous system. Orally administered CP-99,994 potently blocked (ID50 = 4 mg/kg) the leakage of Evans blue dye into trachea and bronchi elicited by exposure of guinea pigs to aerosol capsaicin (1 mM). CP-99,994 has reduced affinity (IC50 = 3 microM) for the L-type calcium channel in contrast to CP-96,345 (IC50 = 27 nM) an earlier nonpeptide antagonist. Thus, CP-99,994 represents an important pharmacological tool for investigating the physiological role of substance P and a potentially novel therapeutic agent for treating a variety of diseases.

Animals↗
PubMed1991

Arylamine spider toxins antagonize NMDA receptor-mediated synaptic transmission in rat hippocampal slices.

The effects of arylamine spider toxins on synaptic transmission in rat hippocampal slices were investigated. Two different responses were monitored: the AMPA receptor-mediated population spike recorded in control buffer (selectively antagonized by DNQX) and the NMDA receptor-mediated EPSP recorded in nominally magnesium-free buffer containing 20 microM DNQX (selectively antagonized by AP5, AP7, and dizocilpine (MK-801)). The synthetic arylamine spider toxins JSTX-3, argiotoxin-636, and argiotoxin-659 were 26 to 73 times more potent at antagonizing the NMDA receptor-mediated EPSP (IC50 values ranging from 12 to 24 microM) than the AMPA receptor-mediated population spike (IC50 values ranging from 612 to 878 microM). These results indicate that arylamine spider toxins are selective antagonists of NMDA receptors in the mammalian CNS.

Animals↗
PubMed1989

Echothiophate and cogeners decrease the voltage dependence of end-plate current decay in frog skeletal muscle.

The effects of three irreversible anticholinesterase agents, echothiophate (217MI), tertiary methylamine analog of 217MI (217AO) and Tetram, on end plate currents (e.p.c.s) of Rana pipiens cutaneous pectoris muscle were studied using electrophysiological techniques. All three compounds (217MI, 1-10 microM; 217AO, 1-25 microM; and Tetram, 1-50 microM) decreased the rate of e.p.c. decay (alpha) to the same extent as neostigmine (10 microM), a reversible anticholinesterase agent. Decay remained a single exponential at all membrane potentials. 217MI and its derivatives greatly reduced the normal voltage dependence of alpha represented by the slope (H = mV-1) of log alpha vs. membrane potential, in contrast to neostigmine which had no effect on H. Suppression of Ach release by the addition of 4 mM Mg++ to end-plates did not alter the reduction of H by 217AO indicating that the anticholinesterase-induced decrease in H is not simply due to an increased interaction between Ach and its receptors. Additionally, the pretreatment of end-plates with methanesulfonyl fluoride, also an irreversible cholinesterase agent, did not modify the effects of 217AO and Tetram on H. 217MI and its derivatives, at low concentrations which altered H, did not affect [3H]PCP or [125I]alpha-bungarotoxin binding to Torpedo californica Ach receptor-rich membranes. It is concluded that these agents alter H by an effect on the Ach receptor ion channel complex unrelated to either esterase inhibition or channel block.

Acetylcholinesterase↗
PubMed1982

Ketamine and ditran block end-plate ion conductance and [3H]phencyclidine binding to electric organ membrane.

Alterations by ketamine (10-100 microM) and ditran (50-100 microM) of end-plate currents were studied using transected cutaneous pectoris muscles. Both drugs reduced peak current and shortened the time constant for end-plate current decay (tau). Ketamine was more effective at pH 5.3 than at 7.4 or 9.1. Recovery from blockade was asymmetrical in that tau recovered more quickly than did peak current when the drugs were removed from the bath. By contrast, 4-aminopyridine antagonized the depression of peak current by ketamine, but not the reduction of tau. Both ketamine and ditran disrupted the voltage dependence of tau. The binding to microsacs prepared from electric organs of [3H]phencyclidine ([3H]PCP) was blocked by ketamine and ditran. In microsacs treated with carbachol, the IC50 for ketamine block of [3H]PCP binding was 6.6 X 10(-6) M. For ditran, the IC50 for block of [3H]PCP binding in the presence of carbachol was 1.7 X 10(-6) M. The binding of [alpha-125I]bungarotoxin to the microsacs or to the cultured chick myotubes was reduced only slightly by ketamine. Because ketamine has no effect on transmitter release and little effect on [alpha-125I]bungarotoxin binding, it is concluded that, like PCP, ketamine and ditran block open channels in the end-plate. In addition, the asymmetrical recovery of end-plate current parameters suggests that ketamine may block closed channels. The recovery from block of closed channels (caused by either a direct action on closed channels or a very slow channel unblocking rate) proceeds more slowly than does the block of open channels.

Animals↗
PubMed1981

Characterization of end-plate conductance in transected frog muscle: modification by drugs.

Cutaneous pectoris muscles of Rana pipiens were transected distal to the innervated region. Within 10 min, membrane potentials (Em's) of -33 +/- 2.5 mV and end-plate potentials (3-15 mV) were recorded unaccompanied by muscle action potentials or twitch. The fall in Em was associated with a net loss of [K+]i and a net gain of [Na+]i. Although input resistance fell by 50% and the space constant was slightly reduced in the transected muscle fibers, end-plates could be adequately voltage-clamped with two microelectrodes. End-plate currents (e.p.c.s) with rise times of 350 to 700 musec were recorded as a function of holding potential (Vm). The current-voltage relationship of peak e.p.c.s over the range of -70 to +20 mV was linear and the reversal potential (-6.6 +/- 2.2 mV) was the same as that found for intact muscle fibers. The decay phase of e.p.c.s could be described as a single exponential at all Vm's and had a voltage and temperature dependence similar to that described for e.p.c.s of glycerol-treated muscles. Tubocurarine (0.3 microM) caused a significant decrease in the time constant (tau) of e.p.c. decay and e.p.c. amplitude. The depression of e.p.c. amplitude by tubocurarine was reversed by 4-aminopyridine while the decrease of tau was not. Atropine (10(-4) M) caused a monotonic shortening of e.p.c.s at a Vm of -90 mV but e.p.c.s recorded at +50 mV were biphasic. Lidocaine, a quaternary nitrogen analog of lidocaine (QX314), lobeline and hexafluorenium were studied also in transected muscle and their effects on the parameters of e.p.c. are described. Both lobeline (50 microM) and hexafluorenium caused a decrease of tau and eliminated the voltage dependence of tau at negative Vm's. The transected muscle can be used for the study of conductance kinetics of end-plate and for the study of drug action uncomplicated by the presence of other drugs of Mg++ to eliminate contraction.

4-Aminopyridine↗