Steric aspects of agonism and antagonism at beta-adrenoceptors: synthesis of and pharmacological experiments with the enantiomers of formoterol and their diastereomers.

The enantiomers of formoterol (R;R and S;S) and their diastereomers (R;S and S;R) were synthesized and purified using a new procedure which required the preparation of the (R;R)- and (S;S)-forms of N-(1-phenylethyl)-N-(1-(p-methoxyphenyl)-2-propyl)-amine as important intermediates. The enantiomeric purity obtained was greater than 99.3%, usually greater than 99.7%. The four stereoisomers were examined with respect to their ability to interact in vitro with beta-adrenoceptors in tissues isolated from guinea pig. The effects measured were (1) relaxation of the tracheal smooth muscle (mostly beta 2), (2) depression of subtetanic contractions of the soleus muscle (beta 2), and (3) increase in the force of the papillary muscle of the left ventricle of the heart (beta 1). All enantiomers caused a concentration-dependent and complete relaxation of the tracheal smooth muscle which was inhibited by propranolol. The order of potency was (R;R) much greater than (R;S) = (S;R) greater than (S;S). There was a 1,000-fold difference in potency between the most and the least potent isomer. The presence of the (S;S)-isomer did not affect the activity of the (R;R)-isomer on the tracheal smooth muscle. Also on the skeletal and cardiac muscles (R;R)-formoterol was more potent than its (R;S)-isomer. The selectivity for beta 2-adrenoceptors appeared to be slightly higher for the (R;R)-isomer than for the (R;S)-isomer. The potency of the (S;R)- and (S;S)-isomers on the papillary muscle was too low to be determined accurately.(ABSTRACT TRUNCATED AT 250 WORDS)

Tritiated methylmercury in the brain of squirrel monkeys.

Tritiated methylmercuty hydroxide (MeHgOH) with a specific activity of 306 curies/mol was synthesized by a Grignard reagent from tritiated methyl iodide with a yield of 70%. Tritiated MeHg was given to squirrel monkeys by stomach tube in weekly doses of 0.8 mg/kg. The animals were killed after one dose or six doses. The distribution of the substance in the brain was then studied by microautoradiography and by fractionation of brain tissue into cellular and subcellular fractions. Part of the MeHg in the brain is in a water-soluble form. Methylmercuty was found autoradiographically mainly in the neuropile of the cortex. At subtoxic doses (one dose), more protein-bound radioactivity was found in the glial fraction than in the neuronal fraction. At toxic dose (six doses), the protein-bound fraction of MeHg increased significantly (P less than .02) in the neurons relative to nontoxic dose (one dose). Methylmercury was demonstrated autoradiographically in damaged neurons but not in undamaged neurons.