Pyrroloquinoxaline Derivatives as High-Affinity and Selective 5-HT₃ Receptor Agonists:  Synthesis, Further Structure−Activity Relationships, and Biological Studies

Abstract

The synthesis, pharmacological evaluation, and structure-activity relationships (SARs) of a series of novel pyrroloquinoxalines and heteroaromatic-related derivatives are described. The new pyrroloquinoxaline-related ligands were tested in rat cortex, a tissue expressing high density of 5-HT(3) receptors, and on NG108-15 cells and exhibited IC(50) values in the low nanomolar or subnanomolar range, as measured by the inhibition of [(3)H]zacopride binding. The SAR studies detailed herein delineated a number of structural features required for improving affinity. Some of the ligands were employed as "molecular yardsticks" to probe the spatial dimensions of the lipophilic pockets L1, L2, and L3 in the 5-HT(3) receptor cleft, while the 7-OH pyrroloquinoxaline analogue was designed to investigate hydrogen bonding with a putative receptor site H1 possibly interacting with the serotonin hydroxy group. The most active pyrroloquinoxaline derivatives showed subnanomolar affinity for the 5-HT(3) receptor. In functional studies ([(14)C]guanidinium accumulation test in NG108-15 hybrid cells, in vitro) most of the tested compounds showed clear-cut 5-HT(3) agonist properties, while some others were found to be partial agonists. Several heteroaromatic systems, bearing N-substituted piperazine moieties, have been explored with respect to 5-HT(3) affinity, and novel structural leads for the development of potent and selective central 5-HT(3) receptor agonists have been identified. Preliminary pharmacokinetic studies indicate that these compounds easily cross the blood-brain barrier (BBB) after systemic administration with a brain/plasma ratio between 2 and 20, unless they bear a highly hydrophilic group on the piperazine ring. None of the tested compounds showed in vivo anxiolytic-like activity, but potential analgesic-like properties have been possibly disclosed for this new class of 5-HT(3) receptor agonists.

Novel Selective 5-HT3 Receptor Ligands: Facile Generation Methods for 2-Amino- and 4-Aminopyrido[4’,3’:4,5]thieno[2,3-d]pyrimidines

“…Furthermore, two singlets appeared at δ = 4.79 and 8.35 ppm corresponding to the NH 2 and NH protons. Three distinctive carbon signals were detected in the 13 C NMR spectrum of 4 at δ = 152.62, 156.16 and 158.24 ppm related to the C-NH 2 and two carbonyl groups (see Experimental Section).…”

“…On the other hand, little is known about the therapeutic potential of 5-HT 3 receptor agonists although some potent and selective ligands with full agonistic properties [13] were recently reported. It has been suggested that stimulation of the 5-HT 3 receptor modulates in the central nervous system the release of dopamine, cholecystokinin, and acetylcholine [14].…”

Development of Small Molecules that Specifically Inhibit the D-loop Activity of RAD51

“…The analogues 9c and 9g were obtained by reducing the nitro group of 9b and 9f 31 via hydrogenation. To synthesize analogues in which the B-ring was replaced with other aromatic or saturated rings, the aniline 5e was reacted with different aldehydes 10a-d under similar conditions (in Scheme 4) to afford the products 11a-d [31][32][33] in good yield.…”

“…31 -The crude product of 4b was further purified by flash silica gel column chromatography (ethyl acetate-hexanes, gradient up to 1:2) to provide the product as orange solid (59%). 1 …”

Quinoxalinylethylpyridylthioureas (QXPTs) as Potent Non-Nucleoside HIV-1 Reverse Transcriptase (RT) Inhibitors. Further SAR Studies and Identification of a Novel Orally Bioavailable Hydrazine-Based Antiviral Agent

“…9 The lactams 9a-g were prepared according to previously described procedures. [10][11][12][13][14] Usually the O-alkylated products were obtained in 10-25% yield. After examination of several reduction methods, we found that treatment of azides 10a-g and 13d,h,i with 1,3-propanedithiol-triethylamine in methanol 15 provided the corresponding amines 11a-g and 14a-c. Last, by treatment of 11a-g and 14a-c with 2-(5-bromopyridyl)isothiocyanate in the presence of triethylamine we obtained the thioureas 12a-g and 15a-c.…”