Design and Synthesis of trans-N-[4-[2-(6-Cyano-1,2,3,4-tetrahydroisoquinolin-2- yl)ethyl]cyclohexyl]-4-quinolinecarboxamide (SB-277011):  A Potent and Selective Dopamine D₃ Receptor Antagonist with High Oral Bioavailability and CNS Penetration in the Rat

Abstract

A selective dopamine D(3) receptor antagonist offers the potential for an effective antipsychotic therapy, free of the serious side effects of currently available drugs. Using clearance and brain penetration studies as a screen, a series of 1,2,3, 4-tetrahydroisoquinolines, exemplified by 13, was identified with high D(3) affinity and selectivity against the D(2) receptor. Following examination of molecular models, the flexible butyl linker present in 13 was replaced by a more conformationally constrained cyclohexylethyl linker, leading to compounds with improved oral bioavailability and selectivity over other receptors. Subsequent optimization of this new series to improve the cytochrome P450 inhibitory profile and CNS penetration gave trans-N-[4-[2-(6-cyano-1, 2,3, 4-tetrahydroisoquinolin-2-yl)ethyl]cyclohexyl]-4-quinolinecarbo xamide (24, SB-277011). This compound is a potent and selective dopamine D(3) receptor antagonist with high oral bioavailability and brain penetration in the rat and represents an excellent new chemical tool for the investigation of the role of the dopamine D(3) receptor in the CNS.

Structure–Activity Study of N-((trans)-4-(2-(7-Cyano-3,4-dihydroisoquinolin-2(1H)-yl)ethyl)cyclohexyl)-1H-indole-2-carboxamide (SB269652), a Bitopic Ligand That Acts as a Negative Allosteric Modulator of the Dopamine D2 Receptor

“…Stemp et al 12 incorporated the 7-cyano substituent to deactivate the THIQ ring system for the purposes of reducing in vivo metabolism, thus increasing oral bioavailability. We determined that replacement of the nitrile group with hydrogen (12b) resulted in a significant 9-fold increase in functional affinity (K B = 87 nM), but no significant change to allosteric cooperativity (Logαβ = -1.04 ± 0.14) at the D 2 R ( Table 1).…”

“…8 More recently, concomitantly targeting both orthosteric and allosteric sites with bitopic ligands, in which allosteric and orthosteric pharmacophores have been linked together, has been explored as a means of developing more selective GPCR ligands. [9][10][11] SB269652 (1) 12,13 was recently described as the first small molecule negative allosteric modulator of the D 2 R. 13 This was somewhat surprising, given that 1 contains structural features of numerous orthosteric D 2 -like receptor ligands. 12,[14][15][16] Indeed, the 1,2,3,4-tetrahydroisoquinoline (THIQ) 'head' group of 1 contains a basic tertiary amine that is expected to form a salt bridge with the conserved aspartate (Asp 3.32 , Ballosteros-Weinstein nomenclature 17 ) of aminergic GPCRs, and would thus compete with the binding of dopamine.…”

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

“…SB-277011-A is a potent and competitive antagonist, with pK b 8.4 (4 nM) in the microphysiometry in vitro functional assay using human cloned DA D 3 receptors expressed in CHO cells, and it maintains selectivity with respect to DA D 2 receptors (pK b 6.5). SB-277011-A has also been shown to readily penetrate the rat brain with a steady-state brain/ plasma ratio of 3.6:1 [229,283]. In the rat, SB-277011-A has an oral bioavailability of 43%, shows low clearance, and a half-life of 2.0 h. The drug appears to be metabolized by the liver enzyme hepatic aldehyde oxidase [16].…”

The selective dopamine D3 receptor antagonists SB-277011A and NGB 2904 and the putative partial D3 receptor agonist BP-897 attenuate methamphetamine-enhanced brain stimulation reward in rats

“…It is also consistent with prior intravenous drug selfadministration experiments demonstrating that SB-277011A or NGB 2904 dose-dependently inhibits cocaine or nicotine self-administration under PR reinforcement schedules Ross et al 2007) and prevents reinstatement of drug-seeking behavior induced by cocaine or nicotine, drug-related cues, or stress (Vorel et al 2002;Xi et al 2004Xi et al , 2006Andreoli et al 2003;Cervo et al 2007). SB-277011A is a highly potent and selective D 3 receptor antagonist that has 80-to 100-fold selectivity for D 3 over other DA receptors and 100-fold selectivity over 180 other receptors, enzymes, ion channels, and transporters in the central nervous system (Reavill et al 2000;Stemp et al 2000;Micheli and Heidbreder 2006;Heidbreder et al, unpublished data). Similarly, the novel D 3 receptor antagonist NGB 2904 also has >150-fold selectivity for primate D 3 over primate D 2 receptors, >800-fold selectivity for rat D 3 vs rat D 2 receptors, and >5,000-fold selectivity over D 1 , D 4 , and D 5 receptors (Yuan et al 1998;Newman et al 2003).…”