Development of Novel 1,2,3,4‐Tetrahydroisoquinoline Derivatives and Closely Related Compounds as Potent and Selective Dopamine D₃ Receptor Ligands

Abstract

Based on N-alkylated 1,2,3,4-tetrahydroisoquinoline derivatives, which are structurally related to the partial agonist BP 897, a series of novel, selective dopamine D3 receptor antagonists has been synthesised. Derivatisation included changes in the arylamide moiety and the tetrahydroisoquinoline substructure leading to compounds with markedly improved selectivities and affinities in the low nanomolar concentration range. From the 55 structures presented here, (E)-3-(4-iodophenyl)-N-(4-(1,2,3,4-tetrahydroisoquinolin-2-yl)butyl)acrylamide (51) has high affinity (Ki(hD3)=12 nM) and a 123-fold preference for the D3 receptor relative to the D2 receptor subtype. Its pharmacological profile offers the prospect of a novel radioligand as a tool for various dopamine D3-receptor-related in vitro and in vivo investigations.

Pharmacological Analysis Demonstrates Dramatic Alteration of D1Dopamine Receptor Neuronal Distribution in the Rat Analog of l-DOPA-Induced Dyskinesia

“…In such conditions, L-DOPA induces a gradual development of dyskinetic-like AIMs. On day 29, 21 rats were scored as nondyskinetic (score ϭ 0.71), and 44 rats were scored as dyskinetic (score ϭ 8.3) after observation by a trained investigator as described previously (Meissner et al, 2006;Schuster et al, 2008Schuster et al, , 2009) using a validated rating scale (Cenci et al, 1998;Lundblad et al, 2002 (Mach et al, 2004) together with L-DOPA. Doses were chosen for their respective ability to induce D 1 R internalization (Dumartin et al, 1998) and to reduce dyskinesia severity (Bézard et al, 2003).…”

Dopamine D3 Receptor Ligands Block Nicotine-Induced Conditioned Place Preferences through a Mechanism that does not Involve Discriminative-Stimulus or Antidepressant-Like Effects

“…To assess the effects of D 3 R blockade on nicotine's discriminative-stimulus and psychomotor effects, we used a classical two-lever choice drug-discrimination procedure (Colpaert, 1999). Two D 3 R ligands, BP 897, a selective D 3 R partial agonist and ST 198,2,3,-butyl)-3-phenylacrylamide), a recently described D 3 R antagonist, were evaluated with these two procedures at doses selective for the D 3 R. ST 198 presents a 65-fold selectivity for the D 3 over the D 2 receptor (Bezard et al, 2003;Mach et al, 2004): inhibition constants (K i ) are 12 and 780 nM for inhibiting binding to D 3 and D 2 receptors, respectively (Bezard et al, 2003). ST 198 has a lower affinity for human D 1 (K i E25 mM), D 4.4 (K i E5 mM), and D 5 (K i E12 mM) receptors, as well as for a variety of nondopaminergic receptors (Bezard et al, 2003).…”

Synthesis, binding affinity and SAR of new benzolactam derivatives as dopamine D3 receptor ligands

“…The Schmidt reaction, according to the literature, gives benzolactam 3 as the major product; however, by changing the reaction medium from trichloroacetic acid, 16 polyphosphoric acid 17 or sulfuric acid 18 to concentrated hydrochloric acid, 19 the desired benzolactams 2 can be obtained in moderate yields (42%). This reaction was optimized by adding two equivalents of the sodium azide, 20 and it resulted in a 75-85% yield of the benzolactam type 2. Nevertheless, this technique was not useful in case the of the benzosuberone, where the benzolactam 2c was obtained in only a 7% yield, whereas 3c was obtained in an 87% yield.…”