CGP 25454A,a novel and selective presynaptic dopamine autoreceptor antagonist

N-(diethylamino-ethyl)-4-chloro-5-cyano-2-methoxy-benzamide-hydrochloride (CGP 25454A) is a new benzamide derivative now in clinical trials in patients with major depression. Here we describe some basic neurochemical and behavioural properties in animal experiments. In vitro, CGP 25454A increased the field-stimulated [³H]- and [¹⁴C]-overflow from rat striatal slices preloaded with [³H]dopamine and [¹⁴C] choline, indicating that CGP 25454A was able to enhance the release of both dopamine (DA) and acetylcholine (ACh). However, CGP 25454A was 12.9 times more potent in increasing, by 1/6 of the apparent maximal increase, the release of [³H]DA than that of [¹⁴C]ACh. In vivo, CGP 25454A increased [³H]spiperone binding to receptors of the D₂ family in rat striatum by 90–110% (ED₅₀: 13 mg/kg i.p.). As a similar increase in [³H]spiperone binding was found with a variety of agents which increase the synaptic concentration of endogenous DA, the effect of CGP 25454A most probably reflects an enhanced release of DA under in vivo conditions. At 30–100 mg/kg, CGP 25454A inhibited [³H]spiperone binding in the pituitary of the same animals as a result of a blockade of postsynaptic DA receptors. This dual mode of action was also apparent in terms of behavioral changes. At doses as low as 5–10 mg/kg, CGP 25454A produced a weak stimulation, suggested by a trend of increased spontaneous rearing and corroborated by a significant potentiation of the elevated rearing induced by (+)-amphetamine. By contrast, at doses of 30–100 mg/kg, it exerted clear-cut sedative and neuroleptic-like properties. These data obtained from three different experimental approaches suggest that CGP 25454A selectively blocks presynaptic DA autoreceptors in the lower dose range whereas at higher doses it also blocks the postsynaptic receptors.Correspondence to: S. Bischoff at the above address