New Benzo[h][1,6]naphthyridine and Azepino[3,2-c]quinoline Derivatives as Selective Antagonists of 5-HT₄ Receptors:  Binding Profile and Pharmacological Characterization

Abstract

A series of benzo[h][1,6]naphthyridine and azepino[3,2-c]quinoline derivatives were prepared and evaluated to determine the necessary requirements for high affinity on the 5-HT(4) receptors and high selectivity versus other receptors. The compounds were synthesized by substituting the chlorine atom of benzonaphthyridines and azepinoquinolines with various N-alkyl-4-piperidinylmethanolates. They were evaluated in binding assays with [(3)H]GR 113808 as the 5-HT(4) receptor radioligand. The affinity values (K(i) or inhibition percentages) depended upon the substituent on the aromatic ring on one hand and the substituent on the lateral piperidine chain on the other hand. A chlorine atom produced a marked drop in activity while a N-propyl or N-butyl group gave compounds with nanomolar affinities (1 < K(i) < 10 nM). Among the most potent ligands (3a, 4a, 5a), 4a was selected on the basis of its high affinity and selectivity for pharmacological screening and was evaluated in vivo in specific tests. This compound reveals itself as an antagonist/low partial agonist in the COS-7 cells stably expressing the 5-HT(4(a)) receptor. Derivative 4a also showed in vivo potent analgesic activity in the writhing test at very low doses.

Review of 5-HT4R Ligands: State of Art and Clinical Applications

“…5-HT 4 Rs have been also implicated in the modulation of nociception (visceral and cutaneous pain, at least in the rodent) [70,71] and in the modulation of insulin sensitivity and glycemic control in patients with Type II diabetes mellitus [72,73].…”

“…(Fig. 30) We finish this review by considering the derivatives 132 and 133 of our group [71]. Compound 132 is a potent and selective 5-HT 4 R antagonist, with an IC 50 of 0.52 nM.…”

Applications of Multicomponent Assembly Processes to the Facile Syntheses of Diversely Functionalized Nitrogen Heterocycles

“…41 Accordingly, we envisioned that the tetrahydropyridine 48 could serve as a precursor to this fused tricycle by a sequence of olefin isomerization and a Povarov reaction. Although methods for isomerizing tetrahydropyridines to enecarbamates are known, 42 we found that conventional heating of 48 in the presence of 10% Pd/C required lengthy reaction times (24 h) and gave irreproducible yields.…”

3D Pharmacophore, hierarchical methods, and 5-HT4 receptor binding data

“…The definition and comparison of pharmacophores for both 5-HT 3 receptor partial agonists [18] (Figure 2) and 5-HT 4 receptor antagonists ( Figure 3) led to the design of new 5-HT 4 antagonists corresponding to selective compounds 1 and 2 (Scheme 1) [19,20].…”