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)