The inhibition of human platelet 5-hydroxytryptamine uptake by tricyclic antidepressive drugs. The relation between structure and potency

Abstract

Thirty‐five compounds related to the antidepressive drug imipramine in chemical structure have been examined for their capacity to inhibit the uptake of 5‐hydroxytryptamine by human platelets in vitro. Substitution by small‐sized electropositive groups in positions 2 or 3 of a benzene ring gave compounds more active than the prototype, 3‐chloroimipramine being five times as potent on this test. Alteration of the characteristic seven‐membered ring of the antidepressive drugs reduced the activity while substitution in the basic side‐chain destroyed it. The tertiary amines were more potent inhibitors than their demethylated derivatives. In this and other ways the active structure for the inhibition of 5‐ht uptake by human blood platelets differs from that for the inhibition of noradrenaline uptake by the rat heart.

On the pharmacology and biochemistry of the amine‐uptake mechanism in human blood platelets

“…The complete inhibition produced by it and tricyclic anti-depressive compounds (Todrick & Tait, 1969) suggests that they do not inhibit by acting on the Na+/K+-dependent ATPase transport mechanism.…”

“…Except where specifically stated, the techniques used in these experiments were those described previously (Marshall, Stirling, Tait & Todrick, 1960;Yates, Todrick & Tait, 1963;Todrick & Tait, 1969). Platelet-rich plasma, 15 ml, was added to 0 5 ml total volume of solutions of 5-HT, inhibitors and other compounds where required and incubated at 370 C for 20 minutes.…”

“…This uptake is blocked by low concentrations of tricyclic anti-depressive drugs (Todrick & Tait, 1969) which, however, have negligible actions on many enzyme systems (L0vtrup, 1963, 1964). Since the pharmacological action of such drugs cannot be understood without a knowledge of the underlying biochemical processes, identification of the enzymes or other macromolecular components involved in the uptake process has been attempted.…”

Removal of 5‐hydroxytryptamine in the pulmonary circulation of rat isolated lungs

“…These cells can take up 5-HT (Stacey, 1961), the uptake can be blocked by amitriptyline-like drugs (Todrick & Tait, 1969), and they are present in the lung capillaries in large numbers (Kaufman, Airo, Pollock & Crosby, 1965). However, 5-HT taken up by platelets is found in intracellular storage organelles (Born, 1963;Tranzer, Da Prada & Pletscher, 1966) and although platelets will oxidize exogenous 5-HT, the amount of metabolism is small, for example, 3% in platelets incubated with 5-HT (10-6M) for 2 h (Pletscher, Burkard, Tranzer & Gey, 1967).…”

“…The tricyclic antidepressant drugs of the imipramine type inhibit catecholamine and 5-HT uptake in various systems (Todrick & Tait, 1969;Thoenen, Huerlimann & Haefely, 1964). Amitriptyline (10-6-10-5M) or desmethylimipramine (10-5M) infused through the lung reduced the removal of 5-HT so that instead of 8%, between 20 and 50% of the infused 5-HT appeared in the perfusate (Table 1).…”