Synthesis and pharmacology of hydroxylated metabolites of methylphenidate.

threo-dl-p-Hydroxymethylphenidate and erythro-dl-p-hydroxymethylphenidate (5a and 5b) and the deesterified products, threo-dl- and erythro-dl-p-hydroxyritalinic acid (6a and 6b), were synthesized. The effects of the intracerebroventricular administration of these compounds on the locomotor activity of rats was determined and compared to that of the respective racemates of methylphenidate (1a and 1b) and ritalinic acid (2a and 2b) as a relative index of in vivo dopaminergic activity. The maximal locomotor response was significantly greater for 5a than for 5b, 1a, or 1b. These findings suggest that metabolite 5a may play a role in the pharmacology of 1a. The intracerebroventricular administration of acids 2a, 2b, 6a, and 6b all produced a small increase in locomotor activity relative to their methyl esters which was not appreciably affected by stereochemistry or para-hydroxylation.