Design, synthesis and binding affinity of new nicotinic ligands

Abstract

Nicotinic ligands can be potentially useful as drugs for the management of several important pathologies as well as pharmacological tools to characterize nicotinic receptor subtypes. The design of new nicotinic ligands has been carried out by applying the 3D database search method; thus, the Cambridge Structural Database has been scanned with a query consisting in a pharmacophore substructure with 3D constraints. The nicotinic pharmacophoric features have been obtained from the structure of pyrido[3,4-b]homotropane (PHT), which represents a rigid template. The results of the query suggested the aminoalkylquinoline moiety as simple scaffold, and it was further refined using molecular modeling. Some of the synthesized compounds were found to interact with the central nicotinic receptor on rat cerebral cortex, showing affinity in the nanomolar range and displaying analgesic properties. The possible binding mode of these substances with a homology-built model of the nicotinic receptor has been analyzed by means of induced fit studies.

Design, Synthesis, and Preliminary Pharmacological Evaluation of New Quinoline Derivatives as Nicotinic Ligands

“…It is obvious that this is not the only geometrical feature that influences binding because the volume, shape, and electronic distribution of the molecules also play a crucial role in the interaction with the receptor; docking studies have provided a possible explanation for the binding mode on the R4β2 subtype of 3c, as well as of compounds (S)-1b and (S)-1c. 19 Interestingly, compound 3c displays a 48-fold higher affinity for the receptor subtype labeled by [ 125 I]-R-bungarotoxin with respect to that labeled by [ 3 H]-epibatidine. Other quaternary ammonium compounds have been reported so far to show a preference or selectivity for the R7* compared to the R4β2* subtype; 18,39,40 these compounds, being choline derivatives, belong to a chemical class that is different from that of 3c.…”

“…18 The ER of the secondary amines (S)-1a and (R)-1a has not been measured, due to the low affinity of rac-1a. 19 In addition, enantioselectivity is usually low or absent for nicotinic ligands having the pyrrolidine ring as a secondary amine, while it is higher for bicyclic secondary amines such as pyrido [3,4-b]homotropane or anatoxin-a, with the exception of epibatidine and its derivatives. 15,[29][30][31][32][33] The enantiomers of 1b and 1c were also tested for their affinity on R7* receptor; on this subtype, compounds (S)-1b and (R)-1b have K i values in the micromolar range.…”

“…For each compound, secondary, tertiary, and quaternary derivatives were prepared. Preliminary results on compounds 3-5 19 have also shown that "long" derivatives can interact with, and activate, the central nicotinic receptor.…”

Chemistry and Pharmacological Characterization of Novel Nitrogen Analogues of AMOP-H-OH (Sazetidine-A, 6-[5-(Azetidin-2-ylmethoxy)pyridin-3-yl]hex-5-yn-1-ol) as α4β2-Nicotinic Acetylcholine Receptor-Selective Partial Agonists

“…Compound 8 25 is a partial agonist at R4β2-nAChR (K i = 3 nM) that showed some initial promise in the treatment of cognitive problems in AD and ADHD, but its clinical development has been suspended because of its side effects including dizziness and nausea reported in a clinical trial for ADHD, together with little differentiation from placebo discovered in a clinical trial with AD patients. 27,28 Although compound 9 29,30 does not possess a high affinity for nAChR (K i = 132 nM), it showed a promising analgesic activity in mice using the hot-plate test.…”

“…(2) Replacement of the pyridine with other aromatic rings is a strategy exemplified by the discovery of compound 8 (ABT-418) and quinoline 9 . Compound 8 is a partial agonist at α4β2-nAChR ( K i = 3 nM) that showed some initial promise in the treatment of cognitive problems in AD and ADHD, but its clinical development has been suspended because of its side effects including dizziness and nausea reported in a clinical trial for ADHD, together with little differentiation from placebo discovered in a clinical trial with AD patients. , Although compound 9 , does not possess a high affinity for nAChR ( K i = 132 nM), it showed a promising analgesic activity in mice using the hot-plate test. (3) Introduction of various substituents to the pyridine ring can be combined with other structural changes.…”