Clomipramine - Pharmacology

Pharmacology

Clomipramine is a blocker of the following transporters:

• Serotonin transporter (SERT) (K_i = 0.14 nM)
• Norepinephrine transporter (NET) (K_i = 54 nM)
• Dopamine transporter (DAT) (K_i = 3,020 nM)
• Glycine transporter (GlyT/LeuT)

As well as an antagonist/inverse agonist at the following receptors:

In addition clomipramine's active metabolite desmethylclomipramine is known to display the following affinity:

• Norepinephrine transporter (NET) (K_i = <1 nM)

All affinities listed were assayed using human materials except those for 5-HT₃, 5-HT₆, and 5-HT₇ which are for mouse/rat tissues due to human values being unavailable. Though it is unclear whether it has ever been screened, clomipramine may also act on sigma receptors and calcium, potassium, and sodium channels similarly to other TCAs.

Clomipramine possesses the highest in vitro affinity for the SERT of any of the TCAs. While its affinities for sites other than SERT are almost all over 100-fold lower in comparison, clomipramine is used at relatively high doses (25–300 mg) similar to those employed with other TCAs; hence, at clinical doses clomipramine is not a selective serotonin reuptake inhibitor (SSRI) but instead a very, very strong serotonin reuptake inhibitor with additional norepinephrine reuptake inhibitor, antiserotonergic, antiadrenergic, antidopaminergic, antihistamine, and anticholinergic properties and associated side effects. Clomipramine's affinity for the DAT is very low/negligible and it therefore lacks any significant dopamine reuptake inhibitor actions.

It should also be noted that clomipramine's active metabolite desmethylclomipramine is a much more potent norepinephrine reuptake inhibitor than clomipramine itself. As a result, in vivo clomipramine is more balanced of a serotonin-norepinephrine reuptake inhibitor, though with preferential serotonergic actions nonetheless.