In vitro ACTIVITY OF RO363, A β1‐ADRENOCEPTOR SELECTIVE AGONIST

Iakovidis, Dimitri; Malta, Errol; McPherson, Gary E.; Raper, C.

doi:10.1111/j.1476-5381.1980.tb10860.x

Cited by 39 publications

(8 citation statements)

References 21 publications

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“…However, xamoterol has low intrinsic activity at the ß 1 -adrenoceptor [13], and might be more properly considered a selective ß 1 -adrenoceptor antagonist with a high degree of intrinsic activity. Ro 363, another phenoxypropanolamine, shows higher intrinsic activity at the ß 1 -adrenoceptor [see 14] and a high degree of ß 1 -versus ß 2 -adrenoceptor selectivity [15][16][17]. Potency of BRL 25805 in rat atrium appears comparable to that reported for Ro 363 in other ß 1 -adrenoceptor assays [14].…”

Section: Discussionsupporting

confidence: 54%

Activity of N-(Phenethyl)phenylethanolamines at β1 and β2 Adrenoceptors: Structural Modifications Can Result in Selectivity for Either Subtype

Urtishak

McCafferty²,

Zaratin³

et al. 2001

Pharmacology

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A series of phenylethanolamines bearing a 2-[1-phenylpropyl] substituent on the nitrogen atom was evaluated in vitro for activity at β₁- and β₂-adrenoceptors. As previously observed, the presence of 3,4-dihydroxy substitution on phenylethanolamine is required for potent activation of both subtypes, whereas the 3,5-dihydroxy analog showed selectivity for the β₂-subtype. Replacement by a carboxyl group of the 4-hydroxyl group on the aralkyl nitrogen substituent produced only a small reduction in β₁ potency (5-fold), whereas β₂ potency was reduced by more than 100-fold. Hence this structural class includes agonists having either a β₁, nonselective β₁/β₂ or β₂ selectivity profile.

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Section: Discussionsupporting

confidence: 54%

Activity of N-(Phenethyl)phenylethanolamines at β1 and β2 Adrenoceptors: Structural Modifications Can Result in Selectivity for Either Subtype

Urtishak

McCafferty²,

Zaratin³

et al. 2001

Pharmacology

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“…In smooth muscle preparations, xamoterol produced clear 0-adrenoceptor-mediated effects in otor sites in the two tissues. The slope only K+-stimulated uterine preparations from progesnt curve was not different from unity terone pretreated rats, a tissue in which P2-adrenocep- 1984), P2-adrenoceptors (oestrogen-pretreated guineapig uterus, rat vas deferens, oestrogen-pretreated rat uterus; Krstew et al, 1982;Kenakin, 1982) or mixed piand P2-adrenoceptor populations (guinea-pig trachea; Iakovidis et al, 1980;O'Donnell & Wanstall, e present experiments indicate that 1981) subserve inhibitory responses, adrenoceptorcit P-adrenoceptor-mediated cardiac mediated actions of xamoterol were absent. However, )oth muscle relaxant effects in some, xamoterol elicited non-l-adrenoceptor-mediated ind tissue preparations in which it was hibitory actions in guinea-pig ileal and tracheal ironotropic effects were obtained in preparations.…”

Section: Antagonistic Actions At P-adrenomentioning

confidence: 91%

“…Inotropic activity was monitored in electrically driven cat (2 Hz) and guinea-pig (4 Hz) left atrial and guineapig right ventricular strips (1 Hz). Driving stimuli were delivered to the tissues from a Grass S6 stimulator via a platinum punctate electrode using square wave pulses of2.5 ms duration at twice the threshold voltage required to drive the preparations (for further details see Iakovidis et al, 1980).…”

Section: Cardiac Preparationsmentioning

confidence: 99%

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

Malta¹,

Mian²,

Raper³

1985

British J Pharmacology

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IThe effect of xamoterol and (-)-isoprenaline have been compared for their activity at padrenoceptor sites in a number of in vitro cardiac and smooth muscle preparations. 2 Xamoterol produced weak positive chronotropic effects in guinea-pig, rat and cat atria (intrinsic activity < 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 P,-adrenoceptor stimulation. 3 Xamoterol was without P-adrenoceptor-mediated inhibitory effects in guinea-pig ileal, tracheal and uterine preparations and in the rat vas deferens and oestrogen-primed uterus. Weak P2-adrenoceptor-mediated relaxation was obtained in progesterone-primed rat uteri. 4 Xamoterol produced non-specific inhibitory effects in guinea-pig ileal and tracheal preparations.5 Xamoterol acted as a competitive antagonist at P,-(pA2 range = 7.4 to 7.8) and P2-adrenoceptors (pA2 range 5.2 to 6.2) and displaced ['251]-iodocyanopindolol from guinea-pig left atrial (pKD = 7.25) and uterine (pKD 5.24) membrane preparations. 6 It is concluded that xamoterol displays a selective affinity for p,-adrenoceptors. Although its partial agonistic actions are more evident at P,-adrenoceptor sites, like prenalterol, xamoterol displays a degree of tissue rather than receptor-dependent selectivity.

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“…One may argue that we have used isoprenaline which is an agonist of both pI-and P2-adrenoceptors and, in consequence, the ,-adrenoceptor might also be related to PDE type IV. It has however been clearly shown that the stimulation of ,I-adrenoceptors in the airways is without functional effect either in man (Lofdahl & Svedmyr, 1982;1984) or in guinea-pig (Iakovidis et al, 1980;Johansson & Waldeck, 1981 who showed that rolipram or the PDE III/PDE IV inhibitor Org 30029 potentiated the inhibitory effect of fenoterol on the antigen-induced contraction of the passively sensitized human bronchial isolated smooth muscle, whereas the PDE III selective inhibitor milrinone was inactive. Zaagsma et al (1992) also demonstrated that the P-adrenergic inhibition of antigen-induced histamine release from guineapig peripheral lung was potentiated in the presence of rolipram.…”

Section: Discussionmentioning

confidence: 99%

Effects of rolipram and siguazodan on the human isolated bronchus and their interaction with isoprenaline and sodium nitroprusside

Qian¹,

Naline²,

Karlsson³

et al. 1993

British J Pharmacology

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1 The effects of the selective inhibitors of cyclic AMP phosphodiesterase type IV (rolipram) and type III (siguazodan) and their interactions with isoprenaline and sodium nitroprusside have been studied in the human isolated bronchus. 2 On bronchi under resting tone rolipram was, in terms of potency (pD2 = 7.77 ± 0.14, n = 8), very similar to isoprenaline (pD2 = 7.31 ± 0.12, n = 12) and salbutamol (pD2 = 7.12 ± 0.17, n = 10) and approximately 10 fold more potent than siguazodan (pD2 = 6.80 ± 0.12, n = 6). In terms of efficacy (Ema,x expressed as percentage of maximal effect induced by theophylline 3 mM), both rolipram and siguazodan were less efficient (Emax = 74 ± 6.7%, n = 8 and 66 ± 7.5%, n = 6, respectively) than isoprenaline (Emax = 98 ± 0.4%, n = 12) and salbutamol (Emax = 83 + 2.4%, n = 10).3 During precontraction induced by methacholine (3 x 10-M) or acetylcholine (10-3 M), concentration-response curves to rolipram and siguazodan were shifted to the right and maximal effects reduced. Rolipram was more potent than siguazodan and, in terms of efficacy, it was less active. 4 Rolipram 10-8 and 10-M but not siguazodan potentiated the effects of isoprenaline as shown by the shift to the left of the concentration-response curve to isoprenaline. Sodium nitroprusside-induced relaxation was not modified by either drug. 5 These results show that rolipram is a potent relaxant of the human isolated bronchus, potentiating the effects of P-adrenoceptor stimulation and suggest that, as previously demonstrated in other species (guinea-pig, cow) (Tomkinson et al., 1993), there may be a connection between the P2-adrenoceptor subtype, which predominate in human airway smooth muscle, and the cyclic AMP phosphodiesterase type IV.

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In vitro ACTIVITY OF RO363, A β₁‐ADRENOCEPTOR SELECTIVE AGONIST

Cited by 39 publications

References 21 publications

Activity of N-(Phenethyl)phenylethanolamines at β<sub>1</sub> and β<sub>2</sub> Adrenoceptors: Structural Modifications Can Result in Selectivity for Either Subtype

Activity of N-(Phenethyl)phenylethanolamines at β<sub>1</sub> and β<sub>2</sub> Adrenoceptors: Structural Modifications Can Result in Selectivity for Either Subtype

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

Effects of rolipram and siguazodan on the human isolated bronchus and their interaction with isoprenaline and sodium nitroprusside

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