A Thieno[2,3-d]pyrimidine Scaffold Is a Novel Negative Allosteric Modulator of the Dopamine D₂ Receptor

Abstract

Recently, a novel negative allosteric modulator (NAM) of the D-like dopamine receptors 1 was identified through virtual ligand screening. This ligand comprises a thieno[2,3- d]pyrimidine scaffold that does not feature in known dopaminergic ligands. Herein, we provide pharmacological validation of an allosteric mode of action for 1, revealing that it is a NAM of dopamine efficacy and identify the structural determinants of this allostery. We find that key structural moieties are important for functional affinity and negative cooperativity, while functionalization of the thienopyrimidine at the 5- and 6-positions results in analogues with divergent cooperativity profiles. Successive compound iterations have yielded analogues exhibiting a 10-fold improvement in functional affinity, as well as enhanced negative cooperativity with dopamine affinity and efficacy. Furthermore, our study reveals a fragment-like core that maintains low μM affinity and robust negative cooperativity with markedly improved ligand efficiency.

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

“…Drug-like (NAMs) of DA receptors have recently been identified including the scaffold that is the focus of the present study. [13][14][15][16][17][18][19] Our previous study described the pharmacological validation of a virtual ligand screen hit (1, Figure 1), confirming that it binds with low µM functional affinity and exerts its effect via negative allosteric cooperativity, primarily by modulation of dopamine signalling efficacy. 18 Based on the scaffold of 1, we synthesised a small library of structural analogues to further understand key M A N U S C R I P T…”

“…The synthesis of all compounds generally followed established methods for the synthesis of 1 and other related compounds previously reported by our research group. 18 Each compound detailed in this study was easily accessed in four steps (schemes 1-3). Briefly, Scheme 1 depicts the synthesis of selected analogues (9a-j), beginning with Gewald 20 chemistry to facilitate the one-pot construction of the ethyl 2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate (5), 18 followed by cyclisation with formamide (6) to afford the corresponding 5,6,7,8tetrahydrobenzo [4,5]thieno [2,3-d]pyrimidinone (7).…”

“…Briefly, Scheme 1 depicts the synthesis of selected analogues (9a-j), beginning with Gewald 20 chemistry to facilitate the one-pot construction of the ethyl 2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate (5), 18 followed by cyclisation with formamide (6) to afford the corresponding 5,6,7,8tetrahydrobenzo [4,5]thieno [2,3-d]pyrimidinone (7). 18 POCl 3 was employed to convert pyrimidinone M A N U S C R I P T…”

Dopamine Receptor Heteromers: Biasing Antipsychotics

“…However, the development of purely allosteric ligands, which could bias dopamine signaling without competing for binding to the orthosteric site, might be a preferential strategy over the recently developed orthosteric ligands. Indeed, a series of negative allosteric D 2 R modulators, which do not interact with the orthosteric site, but modulate dopamine efficacy, has recently been reported [18]. Such ligands may serve as lead compounds for the development of biased allosteric modulators, which could potentially evolve into more efficacious APDs.…”

Anticancer activity evaluation of thieno[3,2-e][1,2,3]triazolo[1,5-a]pyrimidines and thieno[2,3-e][1,2,3]triazolo[1,5-a]pyrimidine derivatives

“…N 2. P 321-330 doi: http://dx.doi.org/10.7124/bc.000A0F biological activities, gradually increases [4][5][6].…”