5-HT3 receptor antagonists. 1. New quinoline derivatives

Abstract

A series of esters and amides of 1-alkyl-2-oxo-1,2-dihydroquinoline-4- carboxylic acid or 2-alkoxy-quinoline-4-carboxylic acid containing a basic azabicycloalkyl moiety has been synthesized and evaluated for affinity for the [3H]quipazine-labeled 5-HT3 receptors. Most of the esters exhibited 10-fold more potent activity than that of ondansetron (1; Ki = 7.6 nM). Lipophilic substituents at the 1- or 2-position of the quinoline ring enhanced affinity for the receptors. Compounds 21 and 37 showed the highest affinity (Ki = 0.32 and 0.31 nM, respectively) among them. On the other hand, most of the amides showed 100-fold lower affinity than that of the esters. Molecular modeling studies indicated that the carbonyl moiety in 19 (ester) or 31 (amide) was not coplanar to the plane of an aromatic ring (over 20 degrees deviation). Although some of the selected compounds exhibited potent activity in the Bezold-Jarisch (B-J) reflex test, good correlation was not observed between the affinity for the 5-HT3 receptors and the activity in the B-J reflex test (in vivo). From these data, it was suggested that our quinoline derivatives might interact with the 5-HT3 receptors in a different way from that of the reported 5-HT3 receptor antagonists presumably due to the presence of the heterogeneity of the 5-HT3 receptors between brain and heart.

Pharmacological Properties of KF18259, a Novel 5-HT3-Receptor Antagonist, in Rats: Inhibition of the Distal Colonic Function

“…Whereas KF18259 exhibits a high affinity for 5-HT3 receptors (Ki =0 .47 nM) (21), it has no affinity for any other receptors, including 5-HT1i 5-HT2 and 5-HT4 receptors (T. Yoko yama et al, unpublished observations). Therefore, it is un likely that KF18259 inhibited the distal colonic function via a mechanism independent of 5-HT3 receptors.…”

“…KF 18259, endo-(8-methyl-8-aza-bicyclo [3.2.1 ] oct-3-yl) 1 isobutyl 2 oxo 1, 2 dihydro 4 quinolinecarboxylate hydrochloride ( Fig. 1), is a potent and selective 5-HT3 receptor antagonist (21). KF18259 inhibits the [3H]qupa zine binding to 5-HT3-receptor sites in NG108-15 cells and the 5-HT-induced transient bradycardia in rats (21).…”

“…1), is a potent and selective 5-HT3 receptor antagonist (21). KF18259 inhibits the [3H]qupa zine binding to 5-HT3-receptor sites in NG108-15 cells and the 5-HT-induced transient bradycardia in rats (21). In the present study, we determined the effects of KF18259 on wrap-restraint stress-induced defecation, which is an appropriate animal model for IBS (17), the 5 HT-induced von Bezold-Jarisch reflex and the cisplatin-in duced slowing of gastric emptying in rats.…”

Supported Palladium Nanoparticles‐Catalyzed Synthesis of 3‐Substituted 2‐Quinolones from 2‐Iodoanilines and Alkynes Using Oxalic Acid as C1 Source

“…[3] Recently, several different CO surrogates such as formic acid, [4a,b] paraformaldehyde, N-formylsaccharin, [4c] 9-methyl-9H-fluorene-9-carbonyl chloride [4d] have been described to synthesize carbonyl compounds but their application for quinolones still remain undervalued. 2-Quinolones are the versatile scaffolds present in alkaloids and synthetic molecules exhibiting broad spectrum of biological activities [5] and so far, ample efforts have been devoted for the synthesis of variety of substituted 2-quinolones employing both traditional [6] and metal-catalyzed protocols. [7] Transition metal-catalyzed carbonylative approaches provide an alternative access to 2-quinolone synthesis.…”

Synthesis of quinolin-2-ones by an intramolecular Knoevenagel condensation and by tandem Michael–Knoevenagel heterocyclization

“…The investigations led to a remarkable result, but only in practically the last 10-12 years, when new biological targets were discovered and test systems based on them were designed and in practice highly coeffective screening was embodied in the search for new medicinals. It was established that derivatives of quinolin-2-ones may display properties of nonsteroidal selective androgen modulators [2-4] and may show effective action against hepatitis B [5], act as inhibitors of acyl coenzyme A and cholesterol acyltransferase and increase the permeability of calcium activated K + channels [6, 7], display high antiproliferative activity [8][9][10][11] and the ability to bind to 5-HT 3 receptors [12], to receptors of antibiotics [13], and are inhibitors of various types of kinase [14][15][16][17], of farnesyl transferase [18], and affect erectile dysfunction [19]. The established broad spectrum of biological activity of quinolin-2-ones derivatives studied up to the present time, on the one hand, stimulated the search of new medicinals of various profile based on them, and on the other, made urgent the problem of synthesizing new representatives of this class with the prospect of developing for them characteristic forms of biological activity and the potential of using them for practical purposes.…”