Further Studies on the Interaction of the 5-Hydroxytryptamine₃(5-HT₃) Receptor with Arylpiperazine Ligands. Development of a New 5-HT₃Receptor Ligand Showing Potent Acetylcholinesterase Inhibitory Properties

Abstract

Novel arylpiperazine derivatives bearing lipophilic probes were designed, synthesized, and evaluated for their potential ability to interact with the 5-hydroxytryptamine(3) (5-HT(3)) receptor. Most of the new compounds show subnanomolar 5-HT(3) receptor affinity. Ester 6bc showing a picomolar K(i) value is one of the most potent 5-HT(3) receptor ligands so far synthesized. The structure-affinity relationship study suggests the existence of a certain degree of conformational freedom of the amino acid residues interacting with the substituents in positions 3 and 4 of the quipazine quinoline nucleus. Thus, the tacrine-related heterobivalent ligand 6o was designed in an attempt to capitalize on the evidence of such a steric tolerance. Compound 6o shows a nanomolar potency for both the 5-HT(3) receptor and the human AChE and represents the first example of a rationally designed high-affinity 5-HT(3) receptor ligand showing nanomolar AChE inhibitory activity. Finally, the computational analysis performed on compound 6o allowed the rationalization of the structure-energy determinants for AChE versus BuChE selectivity and revealed the existence of a subsite at the boundary of the 5-HT(3) receptor extracellular domain, which could represent a "peripheral" site similar to that evidenced in the AChE gorge.

(Thiazol-2-yl)hydrazone derivatives from acetylpyridines as dual inhibitors of MAO and AChE: synthesis, biological evaluation and molecular modeling studies

“…In detail, compound 4 had an IC 50 of 2.39 mM against hMAO-A and 880.30 nM against hMAO-B, compound 8 possessed an IC 50 of 6.18 mM against hMAO-A and 1393.10 nM against hMAO-B, while the IC 50 values of compound 9 towards hMAO-A and -B were 4.38 mM and 995.88 nM, respectively. Regarding 3-acetylpyridine derivatives (Table 2), the selectivity towards hMAO-B of compounds containing a methyl group (16), a methoxy group (20) and a further phenyl moiety (21) at C4 position of the aryl moiety increased. Moreover, for compound 20 the concentration required for the inhibitory effect on hMAO-B diminished (IC 50 of 427.54 nM).…”

“…In detail, scaffolds containing a propargylamine moiety are of particular interest due to their reported beneficial actions 18,19 . In a previous work we have demonstrated that the concurrent inhibition of this enzyme and the binding to the 5-HT3 receptor can lead to interesting compounds 20 . AChE is a serine hydrolase mainly found at neuromuscular junctions and cholinergic brain synapses 21 .…”

Design, Synthesis, and Biological Evaluation of Imidazo[1,5-a]quinoline as Highly Potent Ligands of Central Benzodiazepine Receptors

“…38,40 On the other hand, target propargylamide derivative 7n was synthesized from tert-butyl ester 7k via acid 7j (Scheme 2).…”

“…This result can be rationalized in terms of interactions between the ester group and the alkyl moiety in position 4 but also with by assuming that the lipophilic pocket can be saturated as previously observed in 5-HT 3 receptors. 38 On the other hand, in the imidazo [1,5-a]quinoline subseries bearing a phenyl group in position 5 (Figure 4), the effects of the substituents in position 4 were highly variable and appeared to depend on the stereoelectronic features of the substituent itself.…”

Design, synthesis and evaluation of 3,4-dihydroxybenzoic acid derivatives as antioxidants, bio-metal chelating agents and acetylcholinesterase inhibitors

“…Then, we decided to use the crystal 1P0I on the basis of informations from the literature 24 . All compounds formedinteractions with Trp82 and/or hydrogen bond with Glu197.…”