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R B Barlow

Publications and source records attributed to R B Barlow.

At least 19 recordsLinked to original sources
PubMed1992

Inactivation of brain cortex muscarinic receptors by 4-diphenylacetoxy-1-(2-chloroethyl) piperidine mustard.

We demonstrated in this study that 4-DAMP [4-diphenylacetoxy-1-(2- chloroethyl) piperidine] mustard, which cyclizes to the aziridinium ion, behaved as a non-selective, non-competitive inhibitor of muscarinic receptors in rat brain cortex. It inactivated to the same extent the M1, M2 and M4 muscarinic receptors present in this tissue, as well as receptors accessible or not accessible to quaternary antimuscarinic drugs. Under mild incubation conditions, the muscarinic receptors in a state with super high affinity for agonists (SH receptors) were less affected by preactivated 4-DAMP mustard than the receptors in the states with lower affinity for agonists (H and L receptors).

Animals↗
PubMed1992

The Limulus-eye view of the world.

The compound lateral eye of the adult horseshoe crab, Limulus polyphemus, views the world with approximately 1000 ommatidia. Their optical properties and orientation determine the eye's resolution, field of view, and light collecting ability. Optic axes of adjacent ommatidia diverge from 1-15 deg with an average value of 5.5 deg yielding an average resolution of 0.1 cycles/deg. Resolution is not uniform across the eye: along horizontal planes, it is maximal in the anterior region of the eye (0.22 cycle/deg) and minimal in the posterior region (0.07 cycle/deg); along vertical planes, it is maximal near or just below the horizon (0.23 cycle/deg) and minimal above the horizon (0.04 cycle/deg). Together the ommatidia of one eye view approximately 60% of the hemispheric world on one side of the body. There is little binocular overlap (< 1% of total field). Ommatidial facets of up to 320 microns in diameter (among the largest known in the animal kingdom) make the eye a superb light collector. Limulus are known to use vision to find mates both day and night. Apparently, the optics of the lateral eye sample a large enough part of the world with sufficient resolution and light-collecting ability for the animal to succeed at this essential task.

Animals↗
PubMed1992

A circadian clock in the Limulus brain transmits synchronous efferent signals to all eyes.

A circadian clock in the brain of the horseshoe crab, Limulus polyphemus, has an important role in the function of the peripheral visual system. At night, the clock transmits neural activity to the lateral, ventral, and median eyes via efferent optic nerve fibers. The activity occurs in synchronous bursts (maximum rate of 2 bursts/s) with individual efferent fibers contributing a single spike in each burst. The circadian efferent activity originates in the protocerebrum. Lateral connections synchronize the efferent activity recorded from the two halves of the protocerebrum, suggesting the existence of bilateral circadian oscillators. Circadian efferent activity survives excision of the brain and isolation of the protocerebrum. We conclude that circadian clock and its complex neural circuitry are fundamental components of the Limulus visual system.

Animals↗
PubMed1992

Visual responses in teleosts. Electroretinograms, eye movements, and circadian rhythms.

We have recorded ocular potentials in response to brief flashes of light from two teleosts, the white perch (Roccus americana) and the green sunfish (Lepomis cyanellus). The animals were respired and maintained in an alert state for up to 2 d. Responses were recorded with corneal and transcleral electrodes. The responses of green sunfish were composed of electroretinogram (ERG) and eye movement potentials, whereas the responses in white perch contained only the ERG. Injection of curare abolished the sunfish eye movement potentials, unmasking the ERG. Observation under infrared illumination established a direct relationship between eye movements and the fast potentials which could be abolished by curare. We found no evidence of circadian changes in the amplitude of the ERG b-wave of either species. However, our results combined with those of a previous study of sunfish ocular potentials (Dearry, A., and B. Barlow, Jr. 1987. J. Gen. Physiol. 89: 745-770) suggest that the sunfish visual system exhibits rhythmic changes in oculomotor responses, which appear to be controlled by a circadian oscillator.

Animals↗
PubMed1992

The contribution of charge to affinity at functional (M3) muscarinic receptors in guinea-pig ileum assessed from the effects of the carbon analogue of 4-DAMP methiodide.

1. 4-Diphenylacetoxy-1:1-dimethyl cyclohexane (carbo-4-DAMP) is the carbon analogue of 4-diphenylacetoxy-N-methylpiperidine (4-DAMP) methiodide. The compounds differ only in that the quaternary nitrogen atom in 4-DAMP methiodide is replaced by a quaternary carbon atom, which is uncharged. 2. Carbo-4-DAMP appears to act competitively at functional (M3) muscarinic receptors in guinea-pig ileum. Estimates of log affinity constant are 6.0 at 30 degrees C and 5.9 at 37 degrees C, i.e. the compound has 0.1% of the affinity of 4-DAMP methobromide. 3. The absence of charge makes little difference to the conformation as determined by X-ray crystallography. The bond lengths and angles are very similar, though the bonds in the cyclohexane ring of carbo-4-DAMP are consistently slightly longer than those in the piperidinium ring of 4-DAMP methiodide, and the presence of the charge slightly reduces the space between molecules. 4. The difference between the affinities of 4-DAMP methobromide and carbo-4-DAMP indicates that the contribution of coulombic forces to the binding between 4-DAMP methiodide and muscarinic (M3) receptors is at least 17 kJ mol-1 (4.1 kcal mol-1) at 37 degrees C. How much this is an underestimate depends upon how much hydrophobic binding is greater with the uncharged compound.

Animals↗
PubMed1991

Visual performance of horseshoe crabs day and night.

A circadian clock modulates the structure and function of the lateral eyes of Limulus polyphemus, greatly increasing their sensitivity at night. During the mating season, male Limulus are visually attracted both day and night to females and objects that resemble females. This paper asks how well Limulus can see day and night, and whether the circadian changes in retinal sensitivity might influence the ability of these animals to find mates. We recorded the visual behavior of male and female horseshoe crabs in the vicinity of an object--a cement hemisphere (29.5 cm diameter) similar in size and shape to a female horseshoe crab--placed in a mating area near Mashnee Dike, Bourne, Massachusetts. Males oriented toward this target from an average distance of 0.94 m during the day and 0.88 m at night; and females appeared to avoid the target. We conclude that males can see potential mates at night almost as well as they can during the day. Apparently the circadian changes in the retina help compensate for the daily changes in illumination in the animal's normal environment. This study provides the first evidence for a role of visual circadian rhythms in an animal's natural behavior.

Animals↗
PubMed1991

The use of 4-diphenylacetoxy-N-(2-chloroethyl)-piperidine (4-DAMP mustard) for estimating the apparent affinities of some agonists acting at muscarinic receptors in guinea-pig ileum.

1. 4-Diphenylacetoxy-N-(2-chloroethyl)-piperidine (4-DAMP mustard), which is known to block muscarinic M3 receptors in preference to muscarinic M2 receptors, was used to estimate the apparent affinity constants of some agonists acting at muscarinic receptors in guinea-pig ileum. Estimates for carbachol and n-pentyl-trimethyl ammonium iodide were similar to published values obtained in similar conditions: those for n-hexyl-trimethyl ammonium iodide were slightly lower. 2. The results for the agonists, n-pentyl- and n-hexyl-trimethyl ammonium iodides and for the partial agonist, n-heptyl-trimethyl ammonium iodide were not as regular as was suggested by Stephenson, though there is an overall increase in apparent affinity with chain length. 3. Estimates of apparent affinity may be affected by hexamethonium, usually present in experiments on ileum. Its absence had little effect on the results with carbachol but reduced the estimates obtained with n-pentyl trimethyl ammonium, which has strong nicotinic effects compared with its muscarinic effects. On ileum treated with tetrodotoxin the values for n-pentyl trimethyl ammonium were similar to those obtained in the presence of hexamethonium (0.28 mM): slightly higher estimates of affinity were obtained in the presence of indomethacin (2.8 microM). The nicotinic effects of n-pentyl ammonium may involve the release of prostaglandins. 4. The estimates of apparent affinity did not depend on the method used to calculate them as the 'null' method and the 'operational' method give similar answers. Estimates of the transducer-ratio for the partial agonist, n-heptyl-trimethyl ammonium iodide, were numerically the same as those of its efficacy. 5. This work illustrates the use of 4-DAMP mustard as a tool for measuring the apparent affinity of agonists acting at muscarinic M3 receptors.

Animals↗
PubMed1990

Efferent control of temporal response properties of the Limulus lateral eye.

The sensitivity of the Limulus lateral eye exhibits a pronounced circadian rhythm. At night a circadian oscillator in the brain activates efferent fibers in the optic nerve, inducing multiple changes in the physiological and anatomical characteristics of retinal cells. These changes increase the sensitivity of the retina by about five orders of magnitude. We investigated whether this increase in retinal sensitivity is accompanied by changes in the ability of the retina to process temporal information. We measured the frequency transfer characteristic (FTC) of single receptors (ommatidia) by recording the response of their optic nerve fibers to sinusoidally modulated light. We first measured the FTC in the less sensitive daytime state and then after converting the retina to the more sensitive nighttime state by electrical stimulation of the efferent fibers. The activation of these fibers shifted the peak of the FTC to lower frequencies and reduced the slope of the low-frequency limb. These changes reduce the eye's ability to detect rapid changes in light intensity but enhance its ability to detect dim flashes of light. Apparently Limulus sacrifices temporal resolution for increased visual sensitivity at night.

Animals↗
PubMed1990

Circadian rhythms in Limulus photoreceptors. II. Quantum bumps.

The light response of the lateral eye of the horseshoe crab, Limulus polyphemus, increases at night, while the frequency of spontaneous discrete fluctuations of its photoreceptor membrane potential (quantum bumps) decreases. These changes are controlled by a circadian clock in the brain, which transmits activity to the eye via efferent optic nerve fibers (Barlow, R. B., S. J. Bolanski, and M. L Brachman. 1977. Science. 197:86-89). Here we report the results of experiments in which we recorded from single Limulus photoreceptors in vivo for several days and studied in detail changes in their physiological and membrane properties. We found that: (a) The shape of (voltage) quantum bumps changes with the time of day. At night, spontaneous bumps and bumps evoked by dim light are prolonged. The return of the membrane potential to its resting level is delayed, but the rise time of the bump is unaffected. On average, the area under a bump is 2.4 times greater at night than during the day. (b) The rate of spontaneous bumps decreases at night by roughly a factor of 3, but their amplitude distribution remains unchanged. (c) The resting potential and resistance of the photoreceptor membrane do not change with the time of day. (d) the relationship between injected current and impulse rate of the second order neuron, the eccentric cell, also remains unchanged with the time of day. Thus the efferent input from the brain to the retina modulates some of the membrane properties of photoreceptor cells. Our findings suggest that the efferent input acts on ionic channels in the membrane to increase the sensitivity of the photoreceptor to light.

Animals↗
PubMed1990

Effects of chain-length and unsaturation on affinity and selectivity at muscarinic receptors.

1. Lengthening the chain in diphenylacetylcholine decreases affinity for muscarinic cholinoceptors in guinea-pig ileum. Diphenylacetoxypropyldimethylamine and its quaternary trimethylammonium salt are roughly equiactive: the dimethylamine and the piperidine have some selectivity for ileum compared with atria, but are not as active nor as selective as 4-diphenylacetoxy-N-methylpiperidine (4-DAMP) methobromide (MeBr). With the weaker diphenylacetoxybutyl compounds the base is more active than the quaternary salt. 2. The diphenylacetoxybutyl-, cis-butenyl and trans-butenyl compounds have similar affinities. The quaternary salts are less active than the tertiary bases, but they are less selective than the butynyl analogues studied in earlier work. 3. 1,1-Diphenyl-1-hydroxy-2,4-hexadiynyl dimethylamine and its trimethylammonium salt are inactive in concentrations below 100 microM, as are the (+)-camphor-sulphonyl ester of 4-hydroxy-N-methyl piperidine and its methiodide. The (+/-)-phenylcyclopentylacetyl ester of 4-hydroxy-N-methylpiperidine methobromide is more active than its cyclohexyl analogue and than 4-DAMP MeBr but it is less selective than 4-DAMP MeBr. 4. The high selectivity of p-fluoro-hexahydrosila-diphenidol is confirmed but this compound has relatively low affinity (for ileum log K = 7.8). 5. The results indicate steric constraints to binding at muscarinic receptors which could be used to check molecular modelling of the receptor based on its known amino acid sequence. The group binding the charged nitrogen is probably at the mouth of a cavity which can accommodate two large rings (as in 4-DAMP MeBr) but with a depth less than about 7 A so that the rod-like hexadiynes cannot fit. Differences between types of receptor may only involve small changes in geometry secondary to differences in amino acids not directly involved in binding and the production of selectivity depends upon finding substituents which interfere with binding more at one type of receptor than at another.

Animals↗
PubMed1990

Some differential effects of 4-diphenylacetoxy-N-(2-chloroethyl)-piperidine hydrochloride on guinea-pig atria and ileum.

4-Diphenylacetoxy-N-(2-chloroethyl)-piperidine hydrochloride (I) cyclizes at neutral pH to form an aziridinium salt. The formation and breakdown of the salt depend on the temperature (in the range 25 to 37 degrees C). In solution at 30 degrees C, peak levels, corresponding to 60-80% conversion, are reached after around 60 min and the half-life exceeds 100 min. In the presence of 0.9% NaCl conversion was reduced to 45-60%. I blocks muscarinic receptors in guinea-pig ileum and atria irreversibly and it is possible to produce dose-ratios on ileum with 10 nM I which are about 100 times those on atria. After about 30 min exposure to solutions of I (prepared 15-20 min previously so that formation of aziridinium ions is well-established) the graph of log (dose-ratio) against time is linear and similar plots were obtained with two different agonists, carbachol and ethoxyethyltrimethylammonium. With results for the ileum, extrapolation of the line suggests that it does not start from zero (dose-ratio = 1): this is because of an initial relatively rapid reversible block. This early phase is similar to that seen on ileum with 10 nM 4DAMP methobromide, which is a competitive antagonist, so is probably caused by competitive block by the aziridinium ion, which closely resembles 4DAMP metho-salts. The subsequent irreversible phase should be caused by alkylation of the receptors. I is easy to make and should be a valuable tool for the study of muscarinic receptors.

Animals↗
PubMed1989

A comparison of the crystal structures of some quaternary trimethylammonium salts related to dopamine and noradrenaline with those of the corresponding amines: a comment on their nicotine-like biological activities.

The crystal structures of seven substituted phenethylammonium salts and one (phenylpropyl)-ammonium salt have been determined. (I) Trimethyl(phenethyl)ammonium iodide, C11H18N+.I-, Mr = 291.2, orthorhombic, P2(1)2(1)2(1) (No. 19), a = 6.040 (2), b = 7.689 (2), c = 26.528 (9) A, V = 1232 (1) A3, Z = 4, Dx = 1.56 g cm-3, Mo K alpha radiation (lambda = 0.71073 A), mu = 25.33 cm-1, F(000) = 576, T = 298 K, R (wR) = 0.0302 (0.0305) for 1991 reflections with I greater than 3 sigma (I). (II) (p-Hydroxyphenethyl)trimethylammonium iodide, C11H18NO+.I-, Mr = 307.2, triclinic, P1 (No. 2), a = 9.619 (1), b = 9.926 (1), c = 14.179 (2) A, alpha = 95.24 (1), beta = 97.50 (1), gamma = 98.97 (1) degrees, V = 1317.2 (3) A3, Z = 4, Dx = 1.55 g cm-3, Mo K alpha radiation (lambda = 0.71073 A), mu = 23.79 cm-1, F(000) = 608, T = 298 K, R (wR) = 0.0351 (0.0373) for 4320 reflections with I greater than 3 sigma (I). (III) (m-Hydroxyphenethyl)trimethylammonium iodide hemihydrate, C11H18NO+.I-.1/2H2O, Mr = 316.2, monoclinic, P2(1)/n (non-standard, No. 14), a = 8.048 (2), b = 9.782 (3), c = 17.447 (7) A, beta = 90.15 (1) degrees, V = 1374 (2) A3, Z = 4, Dx = 1.53 g cm-3, Mo K alpha radiation (lambda = 0.71073 A), mu = 22.86 cm-1, F(000) = 628, T = 298 K, R (wR) = 0.0719 (0.0655) for 1006 reflections with I greater than 1 sigma (I).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

The X-ray crystal structure of 4-diphenylcarbamyl-N-methyl-piperidine methobromide (the carbamate analogue of 4-DAMP methiodide).

1. Crystals of 4-diphenylcarbamyl-N-methylpiperidine methobromide contain 2 conformers, one with the ester group equatorial and the other with the ester group axial to the piperidine ring. 2. In both conformers and diphenylcarbamyl nitrogen is trigonally substituted and flat compared with the tetrahedral substitution of the corresponding carbon atom in 4-diphenylacetoxy-N-methylpiperidine (4-DAMP) methiodide. 3. The low activity and selectivity of the carbamate at muscarinic receptors is comparable with that of compounds containing only one phenyl ring, e.g. phenylacetyl-N-methyl piperidine methiodide or phenylacetylcholine. It is suggested that the high affinity of 4-DAMP metho-salts and their selectivity depend upon interactions with groups arranged in three dimensions and that the trigonal arrangement about the nitrogen atom in the carbamate makes it impossible for both benzene rings to interact at once.

Crystallization↗
PubMed1989

Relations between structure and nicotine-like activity: X-ray crystal structure analysis of (-)-cytisine and (-)-lobeline hydrochloride and a comparison with (-)-nicotine and other nicotine-like compounds.

1. Although (-)-cytisine is a rigid structure, it occurs in the crystal in two distinct but very similar conformations in which the pyridone ring is tilted relative to the charged nitrogen atom at much the same angle as the pyridine ring is in (-)-nicotine hydrogen iodide. The carbonyl group in the pyridone ring of (-)-cytisine, however, is on the side of the ring opposite to pyridine nitrogen in (-)-nicotine. 2. The pKa of (-)-lobeline HCl at 25 degrees C is 8.6 (approx), indicating that (-)-lobeline is at least 90% in the protonated form at physiological pH (7.6). It is probably the phenyl 2-keto-ethyl part of (-)-lobeline, rather than the phenyl 2-hydroxy-ethyl part, which interacts with the receptor. 3. The combination within one molecule of a charged ('onium') nitrogen atom lying out of the plane of, and some distance (4.5-6.5 A) from, an aromatic ring is common to many compounds with nicotine-like activity (e.g. nicotine, cytisine, choline phenyl ether bromide, dimethyl-phenyl-piperazinium (DMPP) iodide, coryneine iodide and m-hydroxyphenylpropyl trimethyl ammonium iodide). In some molecules the aromatic ring can be replaced by an unsaturated group, such as carbonyl (e.g. acetylcholine) or double-bonds (e.g. anatoxin). 4. Activity at nicotinic receptors appears to involve interactions between the positively charged nitrogen atom and a negatively charged group, probably close to cysteine residues 192 and 193 in the receptor. It is suggested that rather than specific groups in the molecule also being involved, activity at nicotinic receptors depends on interactions between a flat part of the drug containing double-bonds, or systems of double bonds, and a planar area in the receptor, possibly tyrosine or phenylalanine residues.

Alkaloids↗
PubMed1988

Efferent neurotransmission of circadian rhythms in Limulus lateral eye. II. Intracellular recordings in vitro.

We investigated efferent neurotransmission in the Limulus lateral eye by studying the action of pharmacological agents on responses of photoreceptor cells in vitro. We recorded transmembrane potentials from single cells in slices of retina that were excised during the day and maintained for several days in a culture medium. Potentials recorded in the absence of pharmacological agents resemble those recorded from cells in vivo during the day. Octopamine, a putative efferent neurotransmitter, induced changes in photoreceptor potentials that mimicked in part those generated at night by a circadian clock located in the brain. Specifically, octopamine (100 to 500 microM) decreased the frequency of occurrence of quantum bumps in the dark and increased the amplitude of photoreceptor responses to intermediate and high light intensities. Similar actions were produced by naphazoline (25 to 100 microM, potent agonist of octopamine), forskolin (8 to 400 microM, activator of adenylate cyclase), IBMX (1 mM, inhibitor of phosphodiesterase), and 8-bromo-cAMP (500 microM, analogue of cAMP). 8-bromo-cGMP (500 microM, analogue of cGMP) decreased the rate of spontaneous quantum bumps only. Our results support the hypothesis that (1) octopamine is an efferent neurotransmitter of circadian rhythms in the Limulus eye and that (2) it activates adenylate cyclase to increase levels of the second messenger, cAMP, in photoreceptor cells. Circadian changes in photoreceptor responses to moderate intensities may be a specific action of cAMP, since cGMP has no effect. Circadian changes in the rate of spontaneous quantum bumps may involve a less specific intermediate, since both cAMP and cGMP reduce bump rate. Characteristics of the retinal slice preparation precluded a detailed study of the effects of pharmacological agents on retinal morphology.

1-Methyl-3-isobutylxanthine↗
PubMed1988

The affinity of some acetylenic analogues of 4-DAMP methobromide for muscarinic receptors in guinea-pig ileum and atria.

1. The replacement of 4-hydroxy-N-methyl piperidine (HO NMe) in 4-diphenylacetoxy-N-methyl piperidine (4-DAMP) metho-bromide by 4-hydroxy-but-2-ynylamines (HOCH2C=CCH2NR2) reduces the affinity for muscarine-sensitive acetylcholine receptors in guinea-pig ileum and atria. It does not abolish selectivity. The tertiary amines are more active and more selective than the corresponding quaternary salts. 2. Analogous derivatives of 4-hydroxy-but-2-ynylamines which lack the ester group (i.e. substituted 4-hydroxymethyl-propynyl amines) are less active and less selective. The quaternary compounds are more active than the tertiary bases. 3. The diphenylcarbamyl ester of 4-hydroxy-N-methylpiperidine methobromide has less than one-thousandth of the activity of the diphenylacetyl ester (4-DAMP methobromide) and is not selective. 4. Although 4-diphenylacetoxy-butynyl dimethylamine is only about one-hundredth as active as 4-DAMP methobromide it appears to have comparable selectivity. It is an interesting compound because it is a tertiary amine and should cross membranes.

Animals↗