The "selective" dopamine D1 receptor antagonist, SCH23390, is a potent and high efficacy agonist at cloned human serotonin2C receptors.
BACKGROUND
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.


OBJECTIVE
We examined its functional actions at cloned human (h)5-HT2C receptors (VSV isoform) stably expressed in CHO cells.


METHODS
Since 5-HT2C 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 (Ki, 9.3 nM) at h5-HT2C 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-HT2C 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-HT2C receptors. Activation of 5-HT2C receptors by SCH23390 may contribute to its functional properties both in animals and in humans.
Millan
M J
MJ
Institut de Recherches Servier, Psychopharmacology Department, Paris, France.
Newman-Tancredi
A
A
Quentric
Y
Y
Cussac
D
D
D000818:Animals; D001552:Benzazepines / Q000378:metabolism / Q000494:pharmacology*; D001667:Binding, Competitive / Q000187:drug effects / Q000502:physiology; D016466:CHO Cells; D006224:Cricetinae; D018491:Dopamine Agonists / Q000494:pharmacology*; D018492:Dopamine Antagonists / Q000378:metabolism / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D051381:Rats; D044405:Receptor, Serotonin, 5-HT2C; D017447:Receptors, Dopamine D1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011985:Receptors, Serotonin / Q000378:metabolism* / Q000502:physiology
D001552:Benzazepines; D018491:Dopamine Agonists; D018492:Dopamine Antagonists; D044405:Receptor, Serotonin, 5-HT2C; D017447:Receptors, Dopamine D1; D011985:Receptors, Serotonin