Structureactivity Relations

Sertraline hydrochloride specifically blocks the reuptake of 5-HT in the soma and terminal regions of serotonergic neurons. The ability of sertraline to inhibit 5-HT reuptake is approximately 20-fold higher than its capacity to inhibit uptake of either norepinephrine or dopamine (DA) (Heym and Koe 1988). However, sertraline is more potent at blocking DA receptor uptake than are other selective serotonin reuptake inhibitors (SSRIs) and TCAs (Hiemke and Hartter 2000; Richelson 1994).

Serotonin neurons in the midbrain raphe nuclei have inhibitory autoreceptors in both the soma (serotonin1A [5-HT1A] receptors) and terminal area (serotonin1B [5-HT1B] receptors) that are stimulated by the acute increase in 5-HT. Thus, the immediate effect of serotonin transporter (5-HTT) blockade is to increase the amount of 5-HT in axosomatic synapses and to decrease neuronal firing

(Blier 2001; Blier et al. 1990; Heym and Koe 1988). Over several weeks, these autoreceptors are desensitized and firing rates increase.

Unlike the older TCAs, sertraline has little appreciable antagonistic effect on histamine], (H1), muscarinic, or dopamine2 (D2) receptors and thus is associated with few difficulties with severe constipation, drowsiness, and dry mouth (Hiemke and Hartter 2000; Richelson 1994). The antagonism of ai-adrenoreceptors by sertraline is at least 10-fold more than that of other SSRIs (Hiemke and Hartter 2000), although this antagonism does not translate into clinically meaningful hypotension or reflex tachycardia. However, there is a report suggesting that sertraline decreases sympathetic nervous system activity, a property consistent with a receptor blockade (Shores et al. 2001). It is also possible that the decrease in sympathetic response is related to stimulation of the 5-HT1A receptors noted above. Given that sertraline and other medications in its class exhibit anxiolytic effects, it is possible that the decrease in sympathetic activity is related to these effects.

Sertraline is metabolized to desmethylsertraline (see section "Pharmacokinetics and Distribution" below). This compound is approximately one-tenth as active in blocking the reuptake of 5-HT; it also lacks antidepressant activity in animal models (Heym and Koe 1988).

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