The "selective" dopamine D₁ receptor antagonist, SCH23390, is a potent and high efficacy agonist at cloned human serotonin_2C receptors

Abstract.

Rationale: The benzazepine and "selective" dopamine D₁ receptor antagonist, SCH23390 [(R)-(+)-8-chloro-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1H-benzazepine-7-ol], shows significant affinity at native serotonin (5-HT)_2C receptors. Objectives: We examined its functional actions at cloned human (h)5-HT_2C receptors (VSV isoform) stably expressed in CHO cells. Methods: Since 5-HT_2C receptors are positively coupled to phospholipase C (PLC), their activation was determined by depletion of membrane-bound pools of pre-labelled [³H]phosphotidylinositol ([³H]PI). Results: SCH23390 showed high affinity (K_i, 9.3 nM) at h5-HT_2C sites and depleted [³H]PI with an EC₅₀ of 2.6 nM. Its efficacy was equivalent to that of 5-HT. [³H]PI depletion elicited by SCH23390 was concentration-dependently abolished by the selective 5-HT_2C antagonist, SB242,084, with a K_B of 0.55 nM. Further, in the presence of a fixed concentration of SB242,084 (10 nM), the concentration-response curve for SCH23390 was shifted to the right without loss of maximal effect, yielding a K_B of 0.57 nM. Conclusions: SCH23390 is a potent and high efficacy agonist at h5-HT_2C receptors. Activation of 5-HT_2C receptors by SCH23390 may contribute to its functional properties both in animals and in humans.