Synthesis, binding, and modeling studies of new cytisine derivatives, as ligands for neuronal nicotinic acetylcholine receptor subtypes.
The availability of drug affecting neuronal nicotinic acetylcholine receptors (nAChRs) may have important therapeutic potential for the treatment of several CNS pathologies. Pursuing our efforts on the systematic structural modification of cytisine and N-arylalkyl and N-aroylalkyl cytisines were synthesized and tested for the displacement of [(3)H]-epibatidine and [(125)I]-alpha-bungarotoxin from the most widespread brain nAChRs subtypes alpha(4)beta(2) and alpha(7), respectively. While the affinity for alpha(7) subtype was rather poor (K(i) from 0.4 to >50 microM), the affinity for alpha(4)beta(2) subtype was very interesting, with nanomolar K(i) values for the best compounds. The N-substituted cytisines were docked into the rat and human alpha(4)beta(2) nAChR models based on the extracellular domain of a molluscan acetylcholine binding protein. The docking results agreed with the binding data, allowing the detection of discrete amino acid residues of the alpha and beta subunits essential for the ligand binding on rat and human nAChRs, providing a novel structural framework for the development of new alpha(4)beta(2) selective ligands.
Tasso
Bruno
B
Dipartimento di Scienze Farmaceutiche, Università degli Studi di Genova, Viale Benedetto XV 3, 16139 Genova, Italy.
Canu Boido
Caterina
C
Terranova
Emanuela
E
Gotti
Cecilia
C
Riganti
Loredana
L
Clementi
Francesco
F
Artali
Roberto
R
Bombieri
Gabriella
G
Meneghetti
Fiorella
F
Sparatore
Fabio
F
D000470:Alkaloids / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D001392:Azocines / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D002460:Cell Line; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D018722:Nicotinic Agonists / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D018733:Nicotinic Antagonists / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D011485:Protein Binding; D011487:Protein Conformation; D011807:Quinolizines / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D011978:Receptors, Nicotinic / Q000737:chemistry / Q000378:metabolism*; D013816:Thermodynamics; D000093843:Quinolizidine Alkaloids
D000470:Alkaloids; D001392:Azocines; D008024:Ligands; D018722:Nicotinic Agonists; D018733:Nicotinic Antagonists; D011807:Quinolizines; D011978:Receptors, Nicotinic; C403531:nicotinic receptor alpha4beta2; C004712:cytisine; D000093843:Quinolizidine Alkaloids