α-[(t-Butylamino)methyl]-4-hydroxy-m-xylene-α1, α3-diol (AH.3365): a Selective β-Adrenergic Stimulant

Brittain, R. T.; Farmer, J. B.; Jack, David; Martin, L. E.; Simpson, William

doi:10.1038/219862a0

Cited by 129 publications

(30 citation statements)

References 3 publications

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“…The ratio of unchanged drug to metabolite varies in different species. For example, in the dog most of the drug is excreted unchanged but in the rat excretion of metabolite predominated (Brittain, Farmer, Jack, Martin & Simpson, 1968). The high oral activity of salbutamol is also possible because of its resistance to liver catechol-O-methyl transferase.…”

Section: Discussionmentioning

confidence: 99%

Salbutamol: a new, selective β‐adrenoceptive receptor stimulant

Cullum

Farmer

Jack

et al. 1969

British J Pharmacology

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289

116

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Salbutamol is a β‐adrenoceptive receptor stimulant. Its pharmacological actions are reduced or abolished by β‐receptor antagonists. In anaesthetized animals, salbutamol, given intravenously, was slightly less active than isoprenaline in preventing spasm of bronchial smooth muscle but was considerably less active as a cardiac stimulant and vasodepressor substance. Its duration of action was about 2 to 3 times that of isoprenaline. Salbutamol given by mouth or aerosol to conscious guinea‐pigs, greatly diminished bronchospasm caused by inhalation of acetylcholine. By mouth, salbutamol was more active and had a longer duration than isoprenaline or orciprenaline without affecting heart rate. By aerosol, salbutamol was approximately 10 times as active as isoprenaline and 100 times as active as orciprenaline. Its duration of action was much longer than that of isoprenaline or orciprenaline. Only isoprenaline produced an increase in heart rate by the aerosol route. On isolated guinea‐pig trachea salbutamol had about 1/10 the activity of isoprenaline, on isolated atria about 1/2000.

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Section: Discussionmentioning

confidence: 99%

Salbutamol: a new, selective β‐adrenoceptive receptor stimulant

Cullum

Farmer

Jack

et al. 1969

British J Pharmacology

Self Cite

289

116

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“…b2-agonists (e.g., salbutamol) were first developed in the 1960s (Brittain et al, 1968;Hartley et al, 1968). By stimulating b2-adrenoceptors in the lungs, they mimic the action of adrenaline causing bronchodilation (Johnson, 1995).…”

Section: Introductionmentioning

confidence: 99%

Salmeterol’s Extremeβ2 Selectivity Is Due to Residues in Both Extracellular Loops and Transmembrane Domains

2014

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Salmeterol is a long-acting b2-agonist, widely used as an inhaled treatment of asthma and chronic obstructive pulmonary disease. It has very high b2-affinity (log K D 28.95) and is very selective for the b2-adrenoceptor (1000-fold selectivity over the b1-adrenoceptor). This study used a mutagenesis approach to determine the exact amino acids in the human b2-adrenoceptor responsible for this very high selectivity. Wild-type b2-and b1-adrenoceptors, chimeric b2/b1-adrenoceptors, and receptors with single-point mutations were transfected into Chinese hamster ovary-K1 cells, and affinity and function were studied using [ ]cAMP accumulation. Extracellular loop 3 (and specifically amino acid K305) had the largest single effect by reducing salmeterol's affinity for the b2-adrenoceptor by 31-fold. H296 in transmembrane 6 also had a major effect (18-fold reduction in salmeterol affinity). Combining these, in the double mutant b2-H296K-K305D, reduced salmeterol's affinity by 275-fold, to within 4-fold of that of the b1-adrenoceptor, without affecting the affinity or selectivity of other b2-agonists (salbutamol, formoterol, fenoterol, clenbuterol, or adrenaline). Another important amino acid was Y308 in transmembrane 7, although this also affected the affinity and selectivity of other agonists. F194 in extracellular loop 2 and R304 in extracellular loop 3 also had minor effects. None of these mutations (including the double mutant b2-H296K-K305D) affected the efficacy or duration of action of salmeterol. This suggests that the high affinity and selectivity of salmeterol are due to specific amino acids within the receptor itself, but that the duration of action is at least in part due to other factors, for example lipophilicity.

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“…The drawbacks of isoprenaline have led to synthesis of a number of compounds such as salbutamol (Brittain, Farmer, Jack, Martin & Simpson, 1968;Cullum, Farmer, Jack & Levy, 1969) and terbutaline (Bergman, Persson & Wetterlin, 1969) supposed to be more selective for P2-adrenoceptors in terms of the concept of Lands and his co-workers, or longer-acting than isoprenaline.…”

Section: Introductionmentioning

confidence: 99%