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C Raper

Publications and source records attributed to C Raper.

At least 19 recordsLinked to original sources
PubMed1985

Influence of assay buffer on dissociation constants of drugs at beta-adrenoceptor subtypes.

The present investigation has assessed the influence of assay buffer (Tris versus Krebs) on the abilities of several beta-adrenoceptor agonists and antagonists to displace the radioligand (-)-[125I]iodocyanopindolol [( 125I]CYP) from beta 1-(left atrial) and beta 2- (uterine) adrenoceptor sites. Saturation studies indicated that the dissociation constant (KD) for [125I]CYP at both beta-receptor sites was approximately 2-fold greater in Krebs as opposed to Tris buffer, and that the maximal density of binding sites (Bmax) in atria (but not uterus) was also reduced 2-fold. In general, the KD values for beta-adrenoceptor agonists were more influenced by the type of buffer used than were KD values for antagonists. Agonist KD values at beta 2-adrenoceptor sites were higher in Krebs than in Tris buffer, while at beta 1-adrenoceptor sites, variable changes resulted. The selective affinity of agonists at beta 1- and beta 2-adrenoceptor sites was therefore markedly influenced by the buffer used and could not be predicted from the established beta 1-/beta 2-adrenoceptor selectivity of the agonists as found in organ bath studies.

Adrenergic beta-Agonists↗
PubMed1985

The influence of molecular structure on the affinity and efficacy of some beta-adrenoceptor agonists.

The affinity and efficacy of a number of sympathomimetic amines structurally related to prenalterol and the selective beta 1-adrenoceptor agonist RO363 were determined using a combination of radioligand binding and organ bath techniques. Affinity of the molecules (pKD) was calculated from their ability to displace the radioligand [125I]iodocyanopindolol ([125I]CYP) from beta-adrenoceptor sites in left atrial (beta 1) and uterine (beta 2) membrane homogenates. These pKD values were used to calculate efficacy from the positive inotropic and uterine relaxant responses elicited by the drugs in organ bath experiments. The drugs studied were either arylethanolamines i.e., (-)-isoprenaline (ISO), p-hydroxyisoprenaline (pOH-ISO), compounds XIV and XVI or aryloxypropanolamine-derivatives, i.e., oxymethylene-isoprenaline (OM-ISO), prenalterol and Compound XI which possessed a p-phenol or catechol ring and an isopropyl or a homoveratryl amine substituent. Only ISO, OM-ISO, pOH-ISO and Compound XVI were active as agonists in both tissue preparations. These drugs were partial agonists which exhibited a wide range of pD2 values and did not display any marked selectivity for either beta-adrenoceptor subtype. Compound XI and prenalterol were inactive as agonists and together with the partial agonists behaved as competitive antagonists to ISO in the two preparations. All drugs tested displaced [125I]CYP from beta-adrenoceptor sites, however, there was also a wide range of potency amongst the drugs. Analysis of the structure-affinity and structure-efficacy relationships indicated that removal of the 3-hydroxyl group from the catechol ring reduces both affinity and efficacy without altering the selectivity of the drug for either beta-adrenoceptor subtype.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic beta-Agonists↗
PubMed1985

The in vitro pharmacology of xamoterol (ICI 118,587).

The effect of xamoterol and (-)-isoprenaline have been compared for their activity at beta-adrenoceptor sites in a number of in vitro cardiac and smooth muscle preparations. Xamoterol produced weak positive chronotropic effects in guinea-pig, rat and cat atria (intrinsic activity less than 0.55, (-)-isoprenaline = 1). Positive inotropic effects were obtained in driven left atria of the cat but were absent in guinea-pig left atrial and right ventricular strip preparations. Agonistic effects were due to beta 1-adrenoceptor stimulation. Xamoterol was without beta-adrenoceptor-mediated inhibitory effects in guinea-pig ileal, tracheal and uterine preparations and in the rat vas deferens and oestrogen-primed uterus. Weak beta 2-adrenoceptor-mediated relaxation was obtained in progesterone-primed rat uteri. Xamoterol produced non-specific inhibitory effects in guinea-pig ileal and tracheal preparations. Xamoterol acted as a competitive antagonist at beta 1-(pA2 range = 7.4 to 7.8) and beta 2-adrenoceptors (pA2 range 5.2 to 6.2) and displaced [125I]-iodocyanopindolol from guinea-pig left atrial (pKD = 7.25) and uterine (pKD 5.24) membrane preparations. It is concluded that xamoterol displays a selective affinity for beta 1-adrenoceptors. Although its partial agonistic actions are more evident at beta 1-adrenoceptor sites, like prenalterol, xamoterol displays a degree of tissue rather than receptor-dependent selectivity.

Adrenergic beta-Agonists↗
PubMed1985

Comparison of the Arrhythmogenic Actions of (-)-Isoprenaline, Dobutamine and the selective beta 1-adrenoceptor agonist, (+/-)-(1-[3',4'-dihydroxyphenoxy] -2-hydroxy-[3",4"-dimethoxy phenethylamino]-propane)-oxalate (Ro 363).

In guinea-pig left atrial preparations, concentrations of (-)-isoprenaline and (+/-)-(1-[3',4'-dihydroxyphenoxy] -2-hydroxy-[3",4"-dimethoxyphenethylamino]-propane)-oxalate (Ro 363) causing maximal inotropic responses produced small reductions in effective refractory period. Dobutamine had little effect on the refractory period except at supramaximal inotropic concentrations, when increases in effective refractory period were produced. Isolated perfused heart preparations from guinea-pigs developed arrhythmic contractions following the administration of (-)-isoprenaline, Ro 363 and dobutamine in doses producing 70-100% of their maximal chronotropic responses. The arrhythmogenic activity of the three agonists paralleled their respective beta 1-receptor stimulant properties. In chloralose-anaesthetized cats, the 3 agonists, (-)-isoprenaline, Ro 363 and dobutamine, when compared to epinephrine (adrenaline), were essentially devoid of arrhythmogenic activity in animals in which cardiac sensitization was induced by 3-dimethylamino-2-methyl-2-phenoxypropiophenone hydrochloride (U-0882) or halothane. However, all 3 agonists elicited ventricular arrhythmias following the administration of subarrhythmic doses of ouabain and increased the number of subauricular escape beats which occurred during vagal nerve stimulation in non-ouabain treated animals. In all cases the arrhythmogenic activity of the drugs paralleled their relative activity for eliciting rises in heart rate.

Adrenergic beta-Agonists↗
PubMed1985

Comparison of beta-adrenoceptor populations in cat and guinea-pig left atria.

The subtypes of beta-adrenoceptor present in left atrial preparations from the guinea-pig and cat have been assessed using both responses obtained in organ bath experiments and radioligand binding studies. From the positive inotropic responses to procaterol, the pKB values for practolol using a variety of agonists, and from displacement of [125I]cyanopindolol from left atrial membrane homogenates by the selective beta 1- and beta 2-adrenoceptor antagonists L643,717-01J10 and ICI 118,551, it was concluded that guinea-pig left atria possess only beta 1-adrenoceptors, whilst cat left atria possess both beta 1- and beta 2-adrenoceptor subtypes.

Adrenergic beta-Antagonists↗
PubMed1979

Comparison of pre-junctional alpha-adrenoceptors at the neuromuscular junction with vascular post-junctional alpha-receptors in cat skeletal muscle.

1 Activation of pre-junctional alpha-adrenoceptors at the skeletal neuromuscular junction enhances acetylcholine release whereas activation of such receptors at autonomic nerve endings inhibits transmitter output. In the present study the characteristics of pre-junctional alpha-adrenoceptors at motor nerve terminals have been compared with post-junctional (vascular) alpha-adrenoceptors in the cat hind limb.2 Reversal of partial (+)-tubocurarine blockade of contractions of the tibialis anterior muscle was used to monitor pre-junctional activity and increases in hindlimb vascular resistance to assess post-junctional actions at alpha-adrenoceptors.3 Responses to intra-arterial injections of noradrenaline, adrenaline, phenylephrine, oxymetazoline, methoxamine and clonidine were monitored. Dose-response lines for all the compounds except clonidine were parallel. The latter agent produced only weak and inconsistent effects.4 Ratios of the doses of the agents required to produce pre- and post-junctional effects indicated that oxymetazoline and adrenaline possessed some preferential activity at post-junctional sites, whereas the remaining agents were non-selective in their actions. If dose-ratios with respect to noradrenaline were compared at the two sites none of the compounds possessed a marked degree of selectivity.5 In the presence of phentolamine or tolazoline, dose-response curves to the pre- and post-junctional effects of phenylephrine were shifted to a similar extent. Thymoxamine showed preferential activity as a pre-junctional alpha-receptor antagonist.6 In comparing the results of this study with those of other authors, it is apparent that there are marked differences in the characteristics of pre-junctional alpha-receptors at the skeletal neuromuscular junction and at autonomic nerve endings. The pre- and post-junctional alpha-receptors in skeletal muscle show less divergence.

Animals↗
PubMed1977

Catechol-substituted phenoxypropanolamines: adrenoceptor activity in the anaesthetized cat.

1 The pharmacological actions of racemic noradrenaline, adrenaline, isoprenaline and N-t-butylnoradrenaline have been compared with those of their corresponding derivatives containing an oxymethylene (OXY) link between the ring and ethanolamine side chain. 2 The compounds were tested in the anaesthetized cat for their ability to produce positive chronotropic effects, bronchodilator actions, changes in perfusion pressure in the perfused hind limb and decreases in soleus muscle contractions. 3 All the OXY-derivatives were potent beta-adrenoceptor agonists. The inclusion of the oxymethylene link promotes selectivity for beta1-as opposed to beta2-adrenoceptor activity. 4 In comparison with the parent compounds, the OXY-derivatives of adrenaline and noradrenaline had very weak alpha-adrenoceptor stimulant effects.

Animals↗
PubMed1976

Sympathomimetic-induced effects in the soleus muscle of the guinea-pig.

Sympathomimetic amines reduced the peak tension, time to peak and time to half-relaxation of indirectly elicited twitches of the guinea-pig soleus muscle in vivo. Clonic contractions of the soleus muscle were depressed by the amines. On a molar basis salbutamol and orciprenaline were 5.12 and 80.0 times less potent than (+/-)-isoprenaline in producing these effects. Results obtained with the beta-receptor antagonists propranolol, practolol and H35/25 suggest that the depression in skeletal muscle contractility is due to beta2-adrenoreceptor stimulation. The effects of the amines on twitches and clonic contractions of the guinea-pig soleus muscle are qualitatively similar to those reported previously in the cat soleus muscle preparation, which has been used to assess the possible tremorogenic actions of sympathomimetic bronchodilators. On a quantitative basis the molar dose-ratios of the sympathomimetics used, and the effects of beta-receptor antagonists on the responses, are similar in the two species.

Adrenergic beta-Agonists↗
PubMed1976

Studies using KWD 2058, a derivative of terbutaline in isolated atrial and tracheal preparations from the guinea-pig.

KWD 2058 is a derivative of terbutaline in which the ring hydroxy groups are esterified with isobutyric acid. In guinea-pig atrial and tracheal preparations KWD 2058 produced slowly developing beta-receptor mediated actions which were absent in preparations pretreated with physostigmine. Incubation of KWD 2058 with guinea-pig plasma resulted in the production of a compound which was indistinguishable from terbutaline on both a qualitative and quantitative basis. KWD 2058 produced negative inotropic and chronotropic actions and increased the effective refractory period of guinea-pig atria. In addition, KWD 2058 produced a non-competitive antagonism of chronotropic responses to (--)-isoprenaline in atria. It is concluded that KWD 2058 has no affinity for beta-adrenoreceptors and that any beta-agonistic activity displayed is due to its hydrolysis product, terbutaline.

Animals↗