Synthesis, sar and pharmacology of CP-293,019: A potent, selective dopamine D4 receptor antagonist

Role of Dopamine D4 Receptors in Motor Hyperactivity Induced by Neonatal 6-Hydroxydopamine Lesions in Rats

“…Pretreatment of 6-OHDA-lesioned rats with methysergide did not affect their motor responses to subsequent injection of CP-293,019 (Figure 4), suggesting that the behavioral effects of the D 4 antagonist were not mediated by increased release of 5-HT. Methysergide alone failed to affect lesion-induced hyperactivity, further indicating that the motor-inhibiting effects of CP-293,019 in lesioned rats were not related to its moderate potency at 5-HT 1A and 5-HT 2A receptors (Ki ϭ 150 and 500 nM, respectively; Sanner et al 1998). Instead, these findings indicate that CP-293,019 antagonized lesion-induced hyperactivity by a mechanism distinct from that of stimulants.…”

“…A contribution of D 2 receptor blockade to behavioral effects of CP-293,019 seems very unlikely since this agent interacts very weakly at D 2 receptors (Ki Ͼ3.0 M; Sanner et al 1998). In addition, our recent studies indicated that CP-293,019 did not alter rotational behavior induced by D 2 receptor agonists in adult rats with unilateral nigrostriatal DA lesions (Zhang et al 2001).…”

“…In addition, the severity of lesion-induced hyperactivity was highly correlated with the extent of the apparent up-regulation of D 4 , but not D 2 receptors (Figure 2), further implicating impaired development of D 4 receptors in abnormal behaviors induced by the lesions. The role of up-regulated D 4 receptors in motor hyperactivity was further investigated by assessing the behavioral effects of a D 4 -selective antagonist and agonist (Sanner et al 1998;Zorn et al 1997). The D 4 antagonist CP-293,019 dose-dependently reversed lesioninduced motor hyperactivity without affecting activity in control littermates that received sham lesions ( Figure 3).…”

Topographically Based Search for an “Ethogram” Among a Series of Novel D4 Dopamine Receptor Agonists and Antagonists

“…For this procedure, each rat was observed individually for 5-s periods at 1-min intervals over 15 consecutive minutes, using an extended, ethologically based behavioral checklist. This made possible the determination of the presence or absence of the following individual behaviors (occurring alone or in any combination) in each 5-s period: stillness (motionless, with no behavior evident); sniffing (flaring of nostrils with movements of vibrissae); locomotion (coordinated movement of all four legs resulting in change of location); rearing (of any form); rearing free (front paws raised off floor with motion upward or outward away from any surface); rearing to wall (front paws raised off floor with motion upward or outward toward cage wall); rearing seated (front paws raised off floor from a seated position); sifting (characteristic pattern of coordinated movements of the forepaws through bedding material on cage floor); grooming (of Sanner et al (1998). b Patel et al (1997).…”

“…Among these, CP-293,019 (Mansbach et al 1998;Sanner et al 1998;), L-745,870 Patel et al 1997), NGD 94-1 (Tallman 1998), PNU-101387 (Merchant et al 1996), Ro 61-6270 (Hartman et al 1996), and S 18126 (Millan et al 1998) have received, to date, the more extensive preclinical evaluation, and there is some consensus that they show little or no activity in traditional models of either antipsychotic activity (e.g., DA agonist-induced responsivity and inhibition of conditioned avoidance responding) or of extrapyramidal side effect liability (e.g., induction of catalepsy); there are only limited and, thus far, contradictory data as to whether they seem to be inactive , partially active (Tallman 1998), or active (Mansbach et al 1998) in such newer models as restoration of DA agonist-induced disruption of prepulse inhibition.…”