Interference of enantiomers of lofexidine with alpha-adrenoceptors

Some alpha-adrenoceptor-mediated cardiovascular activities and alpha-adrenoceptor binding affinities for (+)- and (-)-lofexidine (Dexlofexidine and Levlofexidine) have been studied in comparison with racemic lofexidine. In pithed normotensive rats, i.v. (-)-lofexidine elicited pressor effects at doses (0.1-30 micrograms/kg), which were approximately 20 times lower than those of the (+)-isomer. Both yohimbine and prazosin in selective amounts of 1.0 and 0.1 mg/kg (i.v., -15 min), respectively, attenuated the increase in diastolic pressure induced by (+/-)-, (+)- and (-)-lofexidine, showing the involvement of alpha 1- as well as alpha 2-adrenoceptors in the vasopressor responses. No differences were observed in the sensitivity of the pressor effects of the (+)- and (-)-enantiomers to blockade by either yohimbine or prazosin. Following i.v. administration to pentobarbitone-anaesthetized normotensive rats, (-)-lofexidine (0.5-5.0 micrograms/kg) was found about 20 times more effective than the dextrorotatory isomer in decreasing mean arterial pressure and heart rate. The increase in heart rate evoked by electrical stimulation in pithed rats was dose-dependently reduced by (+/-)-, (-)- and (+)-lofexidine, the (-)-isomer being about 30 times more potent than the (+)-isomer. Similarly, the electrical stimulation-induced increase in diastolic pressure was also most effectively impaired by the laevorotatory enantiomer of lofexidine. (-)-Lofexidine showed an approximately 9-fold higher affinity than (+)-lofexidine for the alpha 2-adrenoceptor-like binding sites in rat brain membranes identified by [3H]-clonidine and was 4 times more potent at displacing [3H]-prazosin from alpha 1-adrenoceptors. It is concluded that the alpha-adrenoceptor activity of lofexidine resides predominantly in the (-)-isomer. The isomeric activity ratio of the enantiomers of lofexidine (about 20-fold) is higher than normally found for other imidazolines.