ISSN:
1432-1912
Keywords:
Affinity
;
Efficacy
;
β1-/β2-Adrenoceptors
;
Agonists
;
Antagonists
Source:
Springer Online Journal Archives 1860-2000
Topics:
Medicine
Notes:
Summary The affinity and efficacy of a number of sympathomimetic amines structurally related to prenalterol and the selective β1-adrenoceptor agonist RO 363 were determined using a combination of radioligand binding and organ bath techniques. Affinity of the molecules (pK D) was calculated from their ability to displace the radioligand [125I]iodocyanopindolol ([125I]CYP) from β-adrenoceptor sites in left atrial (β1) and uterine (β2) membrane homogenates. These pK D 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 ap-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 β-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 β-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 β-adrenoceptor subtype. While aryloxypropanolamine derivatives have generally higher affinities than arylethanol-amines, especially at β-adrenoceptor sites, their efficacies are generally reduced at both β-adrenoceptors. The presence of a homoveratryl group in aryloxypropanolamines enhances slightly the affinity for β1- and reduces affinity for β2-adrenoceptors. With this amine group, efficacy is markedly reduced at β2- as opposed to β2-adrenoceptor sites. Thus for prenalterol, the small degree of cardioselectivity can be attributed to the oxymethylene group whilst its lack of agonist activity (i.e., efficacy) reflects a combined action of this group and the absence of the 3-hydroxyl group on the phenyl ring. In RO363 it can be deduced that the oxymethylene group, together with the homoveratryl substituent are responsible for the observed selective affinity of the drug for β1- as opposed to β2-adrenoceptors.
Type of Medium:
Electronic Resource
URL:
http://dx.doi.org/10.1007/BF00634244
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