Synthesis and Structure–Activity Relationships of Tool Compounds Based on WAY163909, a 5-HT_2C Receptor Agonist

Abstract

The development of probe molecules that can be used to investigate G protein-coupled receptor (GPCR) pharmacology, trafficking and relationship with other GPCRs is an important and growing area of research. Here, we report the synthesis of analogs of the known selective serotonin (5-HT) 5-HT2C receptor (5-HT2CR) agonist WAY163909 which were designed to allow for the attachment of a second ligand, signaling or reporter molecules as well as immobilization agents to the parent molecule with the maintenance of agonist activity. This goal was accomplished by the synthesis of novel molecules in which sites a–d were modified and resulting compounds were analyzed pharmacologically in vitro.

A General Way to Construct Arene‐Fused Seven‐Membered Nitrogen Heterocycles

“…When the resulting carboxylate solution was neutralized, the desired product precipitated from the solution (additional crystallization was required to obtain these compounds in analytically pure form). In a number of cases (Table 2, entries 13,15,[18][19][20][21][23][24][25][26], we managed to separate the cis and trans diastereomers of compounds 9, and these were characterized individually. As a result, the protocol involving basic extraction followed by neutralization produced impure product mixtures.…”

“…Methyl iodide (355 mg, 2.5 mmol) and K 2 CO 3 (345 mg, 2.5 mmol) were added to this solution. 13 -3-(p-tolyl)-2,3,4,5- 13 -5-oxo-3-phenyl-2,3,4,5-tetrahydrobenzo[f][1,4 13 13 13 -1-oxo-3-(p-tolyl)-2,3,4,5-tetrahydro-1H-benzo[c] The residue was partitioned between water (15 mL) and CH 2 Cl 2 (30 mL).…”

“…10 H) ppm 13. C NMR (101 MHz, CDCl 3 ): δ = 168.7, 167.2, 161.9 (d, J = 247.2 Hz), 153.2, 132.9, 132.8 (d, J = 3.3 Hz), 132.6, 128.1 (d, J = 8.2 Hz), 123.0, 121.8, 119.1, 115.4 (d, J = 21.8 Hz), 81.6, 58.0, 57.0, 52.8, 31.0, 30.2, 26.0, 25.8, 25.4 ppm.…”

“…), 0.93-0.78 (m, 2 H), 0.76-0.64 (m, 1 H) ppm 13. C NMR (101 MHz, CDCl 3 ): δ = 169.3, 168.6, 153.1, 150.3, 137.4, 135.8, 131.4, 128.2, 127.6, 127.2, 126.0, 125.8, 123.5, 121.8, 117.4, 103.6, 81.8, 64.4, 60.7, 56.0, 52.9, 34.0, 8.5, 7.2 ppm.…”

“…1 H NMR (400 MHz, CDCl 3 ): δ = 7.82-7.71 (m, 1 H), 7.54 (td, J = 7.6, 7.1, 2.3 Hz, 1 H), 7.48-7.38 (m, 2 H), 7.21-7.12 (m, 4 H), 4.91 (d, J = 12.1 Hz, 1 H), 4.42 (d, J = 12.1 Hz, 1 H), 3.55 (dq, J = 14.0, 7.0 Hz, 1 H), 3.09 (dq, J = 14.0, 7.0 Hz, 1 H), 2.37 (s, 3 H), 0.97 (t, J = 7.0 Hz, 13 H) ppm 13. M.p.…”