Design and Synthesis of trans-3-(2-(4-((3-(3-(5-Methyl-1,2,4-oxadiazolyl))- phenyl)carboxamido)cyclohexyl)ethyl)-7-methylsulfonyl-2,3,4,5-tetrahydro- 1H-3-benzazepine (SB-414796):  A Potent and Selective Dopamine D₃ Receptor Antagonist

Abstract

At their clinical doses, current antipsychotic agents share the property of both dopamine D(2) and D(3) receptor blockade. However, a major disadvantage of many current medications are the observed extrapyramidal side-effects (EPS), postulated to arise from D(2) receptor antagonism. Consequently, a selective dopamine D(3) receptor antagonist could offer an attractive antipsychotic therapy, devoid of the unwanted EPS. Using SAR information gained in two previously reported series of potent and selective D(3) receptor antagonists, as exemplified by the 2,3,4,5-tetrahydro-1H-3-benzazepine 10 and the 2,3-dihydro-1H-isoindoline 11, a range of 7-sulfonyloxy- and 7-sulfonylbenzazepines has been prepared. Compounds of this type combined a high level of D(3) affinity and selectivity vs D(2) with an excellent pharmacokinetic profile in the rat. Subsequent optimization of this series to improve selectivity over a range of receptors and reduce cytochrome P450 inhibitory potential gave trans-3-(2-(4-((3-(3-(5-methyl-1,2,4-oxidiazolyl))phenyl)carboxamido)cyclohexyl)ethyl)-7-methylsulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine (58, SB-414796). This compound is a potent and selective dopamine D(3) receptor antagonist with high oral bioavailability and is CNS penetrant in the rat. Subsequent evaluation in the rat has shown that 58 preferentially reduces firing of dopaminergic cells in the ventral tegmental area (A10) compared to the substantia nigra (A9), an observation consistent with a prediction for atypical antipsychotic efficacy. In a separate study, 58 has been shown to block expression of the conditioned place preference (CPP) response to cocaine in male rats, suggesting that it may also have a role in the treatment of cue-induced relapse in drug-free cocaine addicts.

S33138 [N-[4-[2-[(3aS,9bR)-8-Cyano-1,3a,4,9b-tetrahydro[1]-benzopyrano[3,4-c]pyrrol-2(3H)-yl)-ethyl]phenylacetamide], a Preferential Dopamine D3versus D2Receptor Antagonist and Potential Antipsychotic Agent. II. A Neurochemical, Electrophysiological and Behavioral Characterization in Vivo

“…Supporting a role of D 3 receptor blockade, the action of S33138 was expressed at low doses similar to those inducing c-fos in limbic structures. Furthermore, a selective reduction in spontaneously active VTA versus SNPC neurones was likewise seen employing highly selective D 3 antagonists (Ashby et al, 2000;MacDonald et al, 2003). Chronic administration of haloperidol may decrease the number of spontane- ously active VTA and SNPC neurones by "depolarization" blockade because manipulations that hyperpolarize neurones, such as apomorphine administration, reverse its effects (Grace et al, 1997).…”

A selective D3 receptor antagonist YQA14 attenuates methamphetamine-induced behavioral sensitization and conditioned place preference in mice

“…All animals were then returned to their home cages without METH or saline treatment for a 7-d withdrawal period (d [14][15][16][17][18][19][20]. Finally, all of the mice were challenged with METH (0.5 mg/kg, ip) on d 21.…”

“…SB-277011A also decreases the breaking point for METH self-administration and METH-induced reinstatement of drug-seeking behavior in rats [13,[16][17][18] . However, further development of SB-277011A as a therapeutic candidate for the treatment of drug addiction has been terminated due to its poor pharmacokinetic profile (an extremely short halflife in primates) and concerns about toxicity [10,19] . Therefore, we have recently developed another novel D 3 R antagonist, YQA14, which binds to two high-affinity binding sites on D 3 Rs with K i values of 0.68×10 -4 nmol/L and 2.11 nmol/L.…”

The role of central dopamine D3 receptors in drug addiction: a review of pharmacological evidence

“…Thus, additional studies are needed to localize the intracerebral site of action for SB-277011-A's protective effects against stress-triggered reinstatement of drugseeking behavior. 4-((3-(3-(5-methyl-1,2,4-oxidiazolyl))phenyl)carboxamido)cyclohexyl)ethyl)-7-methylsulfonyl-2,3,4,5-tetrahydro-1H-3-benzapine (SB-414796), another potent and selective DA D 3 receptor antagonist, can also block the expression of cocaine-induced CPP [186]. Furthermore, the effect of the selective D 3 receptor antagonist NGB-2904 [236,313] has recently been examined in animal models of addiction [309].…”