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. 2022 Dec 2;14(1):18-25.
doi: 10.1021/acsmedchemlett.2c00325. eCollection 2023 Jan 12.

Thienopyrimidine Derivatives as GPR55 Receptor Antagonists: Insight into Structure-Activity Relationship

Laura Figuerola-Asencio  1 , Paula Morales  1 , Pingwei Zhao  2 , Dow P Hurst  3 , Sommayah S Sayed  3 , Katsuya L Colón  3 , María Gómez-Cañas  4 , Javier Fernández-Ruiz  4 , Mitchell P Croatt  3 , Patricia H Reggio  3 , Mary E Abood  2 , Nadine Jagerovic  1
Affiliations

Thienopyrimidine Derivatives as GPR55 Receptor Antagonists: Insight into Structure-Activity Relationship

Laura Figuerola-Asencio et al. ACS Med Chem Lett. .

Abstract

GPR55 is an orphan G-protein coupled receptor involved in various pathophysiological conditions. However, there are only a few noncannabinoid GPR55 ligands reported so far. The lack of potent and selective GPR55 ligands precludes a deep exploration of this receptor. The studies presented here focused on a thienopyrimidine scaffold based on the GPR55 antagonist ML192, previously discovered by high-throughput screening. The GPR55 activities of the new synthesized compounds were assessed using β-arrestin recruitment assays in Chinese hamster ovary cells overexpressing human GPR55. Some derivatives were identified as GPR55 antagonists with functional efficacy and selectivity versus CB1 and CB2 cannabinoid receptors.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
Structure of the putative endogenous GPR55 ligand LPI and the GPR55 hit antagonists ML191, ML192, and ML193 identified by an HTS.
Figure 2
Figure 2
Proposed structural modifications of the thienopyrimidine scaffold.
Scheme 1
Scheme 1. Reagents and Conditions: (i) Gewald Reaction: Ethyl Cyanoacetate, S8, H2O, Et3N, rt, Overnight, 70–87%; (ii; a) Corresponding Nitrile, HCl (4M in dioxane), 4 h Ultrasonic Bath, (b) 100 °C, Overnight, 87–96% [For 7 (85%) and 8 (94%) only procedure A was Applied]; (iii) Morpholine, Dioxane, Et3N, Reflux, Overnight, 53%; (iv) POCl3, 90 °C, 3 h, 60–98%; (v) Corresponding Acylpiperazine, Et3N, Dioxane, Reflux, 24 h, 63–85%; (vi) Morpholine, Dioxane, MW, 120 °C, 3 h, 80% %; (vii) BBr3, CH2Cl2, −78 °C to rt, Overnight, 61–71%
Scheme 2
Scheme 2. Reagents and Conditions: (i) 2-Propanol, 100 °C, Overnight, 51 and 74%
Scheme 3
Scheme 3. Reagents and Conditions: (i) DMSO, 190 °C, 18 h, 5–31%; (ii; a) Acetonitrile, Hydrochloric Acid (12.1 M), 100 °C, 75 min, 24–37%; (iii) POCl3, 150 °C, 3.5 h, 61–94%; (iv; a) Furoylpiperazine, Et3N, Dry MeOH, rt for 24 h, (b) 50 °C for 24 h, 10–18%
Scheme 4
Scheme 4. Reagents and Conditions: (i) 2-Acetylpirydine, KOH (85%), EtOH, Reflux, Overnight, 80%; (ii; a) SOCl2, Reflux, 3 h, (b) 1-(2-Furoyl)piperazine, Et3N, THF, rt, Overnight, 98%; (iii) 1-(2-Furoyl)piperazine, Et3N, Dioxane, Reflux, 24 h, 3–99%; (iii) 1-(2-Furoyl)piperazine, Et3N, Dioxane, Reflux, 24 h, 3–53%; (iv) CH3I, K2CO3, DMF, rt, Overnight, 72%; (v) PyBOP (Benzotriazol-1-yloxytripyrrolidinophosphonium Hexafluorophosphate), DBU (1,8-Diazabicyclo[5.4.0]undec-7-ene), Corresponding Heterocycle, ACN, Overnight, rt, 37–48%
Figure 3
Figure 3
SRE dose response assays of compound 24 (the agonist LPI and the antagonist ML192 were used as reference).
Figure 4
Figure 4
Docking studies of thienopyrimidine derivatives ML192 and 24 in the GPR55 R state (inactive receptor). (A) hGPR55 R/ML192 complex in which the ligand is shown as van der Waals; green tubes highlight residues that establish hydrophobic interactions; purple tubes represent the disulfide bridge formed between the extracellular loops EC3 and EC4. (B) hGPR55 R/compound 24 complex showing the residues establishing hydrophobic interactions with the dimethyl R3 in green tubes.
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