✍ Scribed by Jan Trofast; Kristina ÖSterberg; Britt-Louise Källström; Bertil Waldeck
No coin nor oath required. For personal study only.
The enantiomers of formoterol (R;R and S S ) and their diastereomers (RS and SR) were synthesized and purified using a new procedure which required the preparation of the (RR)and (SS)-forms of N-(l-phenylethyl)-N-(l-(p-methoxyphenyl)-2-propyl)-amine as important intermediates. The enantiomeric purity obtained was greater than 99.3%, usually > 99.7%. The four stereoisomers were examined with respect to their ability to interact in vitro with P-adrenoceptors in tissues isolated from guinea pig. The effects measured were (1) relaxation of the tracheal smooth muscle (mostly &), (2) depression of subtetanic contractions of the soleus muscle (p2), and (3) increase in the force of the papillary muscle of the left ventricle of the heart (pl). All enantiomers caused a concentration-dependent and complete relaxation of the tracheal smooth muscle which was inhibited by propranolol. The order of potency was (RR) > > (RS) = (S;R) > (SS). There was a 1,000-fold difference in potency between the most and the least potent isomer. The presence of the (8s)-isomer did not affect the activity of the (RR)-isomer on the tracheal smooth muscle. Also on the skeletal and cardiac muscles (RR)formoterol was more potent than its (R;S)-isomer. The selectivity for p2 -adrenoceptors appeared to be slightly higher for the (R;R)-isomer than for the (RS)-isomer. The potency of the (SR)-and (SS)-isomers on the papillary muscle was too low to be determined accurately. The present study shows that determination of enantiomeric ratios and conclusions regarding structureeffect relationships are critically dependent on a very high degree of stereochemical purity.
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