The Specificity of Some Agonists and Antagonists for Nicotine‐sensitive Receptors in Ganglia

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I Size in solution can be expressed either as the apparent molal volume at infinite dilution (0') and the concentration parameter (j) or as the partial molal volume of the solute at infinite dilution (V°) and the concentration parameter for the solute or solvent (q, or q%). Although calculated differently, these are derived from the same results and are equivalent.2 From measurements with phenolic quatemary ammonium salts, including compounds with high nicotine-like activity, the apparent size of the hydroxyl group in water is small and variable. Phenolic groups are slightly larger than alcoholic groups, which should be better hydrogen donors. 3 By measuring the volume change associated with ionisation it is possible to measure the size of charged groups such as phenate and carboxylate; these are much smaller than phenolic and carboxyl. Ammonium groups, however, are only slightly smaller than the corresponding amines. 4 The zwitterion forms of amino acids are associated with a minimum in volume but the volume changes increase with chain length from glycine to y-aminobutyric acid. Groups separated by less than this distance interact in their effects on water. 5 Decreases in volume or unexpectedly small increments in apparent molal volume represent decreases in entropy which must be taken into account in drug-water-receptor interactions. Although they may be offset by enthalpy changes, they should favour binding because there is more scope for an increase in entropy. This might explain the association of the small apparent size in water of the hydroxyl group in many compounds with its effects on their affinity for receptors.

Section: Introductionmentioning

confidence: 99%

The Size of Hydroxyl Groups in Solution and the Changes in Size Associated With the Ionization of Phenolic, Carboxylic and Amino Groups in Phenolic Quaternary Ammonium Salts, Nicotine and Some Amino Acids: Possible Implications for Drug‐water and Drug‐receptor Interactions

Barlow¹

1980

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“…From the affinity constant of hexamethonium for the receptors in ganglia in the ileum (Barlow & Franks, 1971) it is possible to calculate the dose-ratios to be expected for any agonist and these are close to the experimental values. This technique has already been used to test the site of action of coryneine (Barlow et al, 1974) which was also included in the present experiments.…”

Section: Resultsmentioning

confidence: 99%

“…In the direct comparisons on the frog rectus the equi- (Barlow et al, 1974) and found the equipotent molar ratio for cinobufotenine relative to coryneine was 3.5 (mean of 3 experiments); the ratio for the trimethylammonium analogue of tryptamine relative to coryneine was 9.9 (mean of 3 experiments).…”

Section: Resultsmentioning

confidence: 99%

“…In this it apparently resembles the quaternary trimethylammonium derivative of dopamine, coryneine (II), which has powerful nicotine-like properties (Barlow, Bowman, Ison & McQueen, 1974) though it has little activity at dopamine receptors (Ginsborg, House & Turnbull, 1976). Neither compound bears a par- ticularly obvious resemblance to nicotine (III), and it is remarkable that the quatemary derivatives of amines with such different biological properties should both activate nicotine-sensitive acetylcholine receptors in parasympathetic ganglia in the ileum.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

A Comparison of Cinobufotenine (The Quaternary Derivative of 5‐ht) and Some Related Compounds With Coryneine (The Quaternary Derivative of Dopamine) on the Frog Rectus, Guinea‐pig Ileum and Rat Fundus Strip Preparations

Barlow¹,

Burston²

1980

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1 Coryneine is 2.7 times as active as cinobufotenine on the frog rectus but on the guinea-pig ileum cinobufotenine is 1.5 times as active as coryneine. Cinobufotenine is a potent stimulant of parasympathetic ganglia and its effects are competitively antagonized by hexamethonium. 2 The effects of pH on activity relative to a standard whose ionisation is constant (Me4N or the trimethylammonium analogue of tryptamine) are consistent with the phenate form being weaker than the phenolic form but the changes are smaller than with coryneine because cinobufotenine is a weaker acid. 3 The hydroxyl group makes a large contribution to activity. Cinobufotenine is 9 times as active as the analogue without a hydroxyl on the frog rectus and 12 times as active as it on the ileum. The 5-methoxy analogue is an antagonist on the frog rectus and a very weak partial agonist on the ileum. 4 Cinobufotenine and the quaternary derivative of tryptamine have less than one-thousandth of the activity of 5-hydroxytryptamine on the rat fundus strip.

“…This was formed inadvertently in the synthesis of leptodactyline (Barlow, Bowman, Ison & McQueen, 1974) and the results of 8 titrations at 37°C in 0.1 M NaCl fitted to the equation pK = pKo + mC4 gave pKo = 8.92. The correct model compound would have the hydroxyl group in the 7 position which is nearer to the quaternary ammonium group and so should be more acidic.…”

Section: Discussionmentioning

confidence: 99%

The Ionization of Morphine, Hydroxy Amphetamine and (+)‐tubocurarine Chloride and a New Method for Calculating Zwitterion Constants

Barlow¹

1982

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1 An improved method for estimating the zwitterion constants of phenolic amines is described which involves the exploratory least-squares fit of absorbance (at a suitable wavelength) to pH, starting with estimates of pKj and pK2 obtained electrometrically.2 With the method it is possible to see that hydroxyamphetamine (oc-methyltyramine) has a higher zwitterion constant than tyramine and the zwitterion constants of both compounds are lower at 37°C than at 25°C. 3 The zwitterion constant of morphine is not reduced by raising the temperature from 250 to 37°C and the effect of temperature is much greater in compounds with a primary or secondary amino group than with those containing a tertiary amino group. Some zwitterions may be stabilized by hydration and their formation will be reduced by a rise in temperature which will break up water structure.4 From electrometric titrations with (+)-tubocurarine chloride in 0.1 M NaCl estimates of pKj, pK2 and pK3 were 7.6, 8.65 and 9.65 at 25°C and 7.4, 8.6 and 9.7 at 37°C, compared with 7.8, 8.85 and 9.75 given by Perrin (1980). However, the effects of pH on absorbance show that the phenolic groups lose a proton before the ammonium group so there is extensive zwitterion formation which is probably greater at 25°than at 37°C. The p-phenolic group (position 13) probably ionizes first with the phenate form stabilized by hydration involving water molecules and the protonated form of the (1-) ammonium group.