Design of novel nicotinic ligands through 3D database searching

Guandalini, Luca; Martini, Elisabetta; Dei, Silvia; Manetti, Dina; Scapecchi, Serena; Teodori, Elisabetta; Romanelli, Maria Novella; Varani, Katia; Greco, Giovanni; Spadola, Loredana; Novellino, Ettore

doi:10.1016/j.bmc.2004.10.039

Cited by 16 publications

(31 citation statements)

References 34 publications

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“…To look for new ideas for the discovery of novel nicotinic ligands, we thought it interesting to apply the 3D database searching approach, 42 a method which was used, although with some differences, almost 20 years ago by Sheridan and Venkataraghavan. 43 Therefore, 44 Among all the output structures found in the hit set, the quinoline derivative VIFLAX 51 (Chart 1) was chosen and its structure simplified in order to give molecules (derived from 7-aminomethylquinoline) able to interact with the nicotinic receptor. Other quinoline derivatives, designed as ligand for the nicotinic receptor, have already been reported in the literature (Chart 2).…”

Section: Resultsmentioning

confidence: 99%

“…Since binding studies showed that only the 6-substituted quinolines possess some affinity (Chart 2, Table 1), a structure optimization study was performed only on compound 1 in order to improve binding affinity: 44 while N-dealkylation or homologation gave inactive compounds (2 and 3, respectively), the freezing of the alkylamino moiety into a pyrrolidine ring was successful since the resulting compound 6 shows nanomolar affinity for the nicotinic receptor of rat cerebral cortex. Quaternarization of the nitrogen then increased affinity of both 1 and 6, although the effects of this modification are different if we consider the cyclic derivative (the affinity of 7 is 3-fold higher that 6) or the linear compound (4 is 40-fold more active than 1).…”

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confidence: 99%

“…Therefore, we designed compounds 8-13: these ligands have pharmacophoric distances greater than 8 Å (the cis alkenes 10 and 13), 9 Å (the trans alkenes 9 and 12) or 10 Å (the butynes 8 and 11). 61 Their synthesis started from 4-(6-quinolinyl)but-3-yn-1-ol 44 which was transformed into the amine via the methanesulfonate and then quaternarized. LiAlH 4 reduction of the triple bond gave a mixture of the cis and trans alkenes in a 1:3 ratio, which was transformed via the methanesulfonate into the corresponding mixture of amines and then separated by column chromatography; the amines were then transformed into the corresponding methiodides (Scheme I).…”

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Design, synthesis and binding affinity of new nicotinic ligands

Guandalini¹,

Martini²,

Gratteri³

et al. 2006

Arkivoc

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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.

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Section: Resultsmentioning

confidence: 99%

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Design, synthesis and binding affinity of new nicotinic ligands

Guandalini¹,

Martini²,

Gratteri³

et al. 2006

Arkivoc

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“…[69] These compounds behave as nicotinic agonists in the hot-plate test on mice when injected i.c.v. [70] Compounds 9 were obtained by optimization of 10 a (R = NMe 2 ) and the methiodide 10 b (R = NMe 3 I), which were designed through a 3D- .…”

Section: Agonistsmentioning

confidence: 99%

“…Their isomers in position 5 or 7 were completely devoid of affinity. [69] Extending the distance between the quinoline and the cationic nitrogen atoms through a butynyl chain gave the compounds with general formula 11. The ammonium derivative 11 a (R = NMe 3 I) was shown to interact with the nicotinic receptor, whereas the corresponding tertiary and secondary amines were devoid of affinity.…”

Section: Agonistsmentioning

confidence: 99%

Central Nicotinic Receptors: Structure, Function, Ligands, and Therapeutic Potential

et al. 2007

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The growing interest in nicotinic receptors, because of their wide expression in neuronal and non-neuronal tissues and their involvement in several important CNS pathologies, has stimulated the synthesis of a high number of ligands able to modulate their function. These membrane proteins appear to be highly heterogeneous, and still only incomplete information is available on their structure, subunit composition, and stoichiometry. This is due to the lack of selective ligands to study the role of nAChR under physiological or pathological conditions; so far, only compounds showing selectivity between alpha4beta2 and alpha7 receptors have been obtained. The nicotinic receptor ligands have been designed starting from lead compounds from natural sources such as nicotine, cytisine, or epibatidine, and, more recently, through the high-throughput screening of chemical libraries. This review focuses on the structure of the new agonists, antagonists, and allosteric ligands of nicotinic receptors, it highlights the current knowledge on the binding site models as a molecular modeling approach to design new compounds, and it discusses the nAChR modulators which have entered clinical trials.

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Immuno‐intervention and preservation of beta‐cell function in type 1 diabetes

Pozzilli

2007

Diabetes Metabolism Res

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The growing interest in nicotinic receptors, because of their wide expression in neuronal and non‐neuronal tissues and their involvement in several important CNS pathologies, has stimulated the synthesis of a high number of ligands able to modulate their function. These membrane proteins appear to be highly heterogeneous, and still only incomplete information is available on their structure, subunit composition, and stoichiometry. This is due to the lack of selective ligands to study the role of nAChR under physiological or pathological conditions; so far, only compounds showing selectivity between α4β2 and α7 receptors have been obtained. The nicotinic receptor ligands have been designed starting from lead compounds from natural sources such as nicotine, cytisine, or epibatidine, and, more recently, through the high‐throughput screening of chemical libraries. This review focuses on the structure of the new agonists, antagonists, and allosteric ligands of nicotinic receptors, it highlights the current knowledge on the binding site models as a molecular modeling approach to design new compounds, and it discusses the nAChR modulators which have entered clinical trials.

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Design of novel nicotinic ligands through 3D database searching

Cited by 16 publications

References 34 publications

Design, synthesis and binding affinity of new nicotinic ligands

Design, synthesis and binding affinity of new nicotinic ligands

Central Nicotinic Receptors: Structure, Function, Ligands, and Therapeutic Potential

Immuno‐intervention and preservation of beta‐cell function in type 1 diabetes

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