Comparative neurotransmitter reuptake and anticholinergic potencies of the 8-hydroxy metabolites of clomipramine.
We hypothesize that 8-hydroxy-clomipramine (8-OH-CMI), the major hydroxy metabolite of clomipramine (CMI), may have antidepressant properties with less anticholinergic potency than CMI. We compared the potencies of 8-OH-CMI and CMI for inhibition of serotonin and norepinephrine reuptake and the potencies of these compounds for blockade of muscarinic receptors. We also compared the antimuscarinic potencies of desmethylclomipramine (DCMI) and 8-hydroxy-desmethylclomipramine (8-OH-DCMI). We found that 8-OH-CMI inhibits the uptake of serotonin and norepinephrine to the same extent as CMI and that 8-OH-CMI has far less antimuscarinic potency than CMI. We also found that 8-OH-DCMI has about one-tenth the antimuscarinic potency of DCMI. Since the therapeutic efficacy of CMI may be related to its effect on the reuptake of neurotransmitters, and since the extent of clinical anticholinergic effects of tricyclic antidepressants has been shown to be related to their in vitro antimuscarinic potencies, these results raise the possibility that 8-OH-CMI may be an analogue of CMI with fewer anticholinergic side effects than the parent compound.
D000818:Animals; D000928:Antidepressive Agents / Q000378:metabolism; D001285:Atropine / Q000494:pharmacology; D002997:Clomipramine / Q000378:metabolism* / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D008297:Male; D018377:Neurotransmitter Agents / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000378:metabolism
D000928:Antidepressive Agents; D018377:Neurotransmitter Agents; D012701:Serotonin; D001285:Atropine; D002997:Clomipramine