Subtle modifications to a thieno[2,3-d]pyrimidine scaffold yield negative allosteric modulators and agonists of the dopamine D2 receptor

Abstract

We recently described a structurally novel series of negative allosteric modulators (NAMs) of the dopamine D 2 receptor (D 2 R) based on thieno [2,3-d]pyrimidine 1, showing it can be structurally simplified to reveal low molecular weight, fragment-like NAMs that retain robust negative cooperativity, such as 3. Herein, we report the synthesis and functional profiling of analogues of 3, placing specific emphasis on examining secondary and tertiary amino substituents at the 4-position, combined with a range of substituents at the 5/6-positions (e.g. aromatic/aliphatic carbocycles). We identify analogues with diverse pharmacology at the D 2 R including NAMs (19fc) with sub-µM affinity (9h) and, surprisingly, low efficacy partial agonists (9d and 9i).

Allosteric Modulators of Dopamine D2 Receptors for Fine-Tuning of Dopaminergic Neurotransmission in CNS Diseases: Overview, Pharmacology, Structural Aspects and Synthesis

“…Logα b (α) Logβ c (β) 2 [34] 5.41 ± 0.22 (3.87) 0 −0.55 ± 0.08 (0.28) 2a [34] 5.55 ± 0.12 (2.81) −1.22 ± 0.16 (0.06) −3.0 2b [34] 6.18 ± 0.16 (0.662) −0.17 ± 0.17 (0.68) −1.10 ± 0.10 (0.08) 2c [34] 5.58 ± 0.10 (1.4) −0.88 ± 0.16 (0.13) −1.21 ± 0.16 (0.06) 2d [35] 6.25 ± 0.12 (0.57) −0.72 ± 0.12 (0.19) −0.65 ± 0.07 (0.22) 2e [35] 5.53 ± 0.13 (2.92) 0 −1.55 ± 0.19 (0.03) In the subsequent work, the same research group showed that subtle modifications to a thieno [2,3-d]pyrimidine scaffold yield negative allosteric modulators of D2 receptor [35]. They obtained NAMs with divergent affinity/cooperativity profiles (see Figure 4 and Table 2).…”

“…Żuk et al [37] performed molecular dynamics simulations, which confirmed that the R enantiomer of compound 3 is a PAM of the D2L receptor, while its S enantiomer is a NAM. Moreover, the authors obtained a derivative of compound 3, compound 3a (see Figure 5) as a racemic mixture and based on the principal component analysis (PCA), they hypothesized that both enantiomers of compound 3a behave as silent allosteric modulators, which In the subsequent work, the same research group showed that subtle modifications to a thieno [2,3-d]pyrimidine scaffold yield negative allosteric modulators of D 2 receptor [35]. They obtained NAMs with divergent affinity/cooperativity profiles (see Figure 4 and Table 2).…”

“…The incorporated changes included exploring the size of the fused carbocyclic ring along with functionalization with single substituents at positions 5 and 6 of the thieno[2,3-d]pyrimidine core. Other modifications relied on removing morpholinomethyl substituent, isosteric replacement of morpholine, varying the length of the methylene linker and transforming the substituent at position 4 in the pyrimidine ring [35,92].…”