Syntheses and evaluation of halogenated cytisine derivatives and of bioisosteric thiocytisine as potent and selective nAChR ligands.
We have developed one-step syntheses of halogenated derivatives of (-)-cytisine featuring a halogen substituent at positions 3, 5 or 3 and 5 of the 2-pyridone fragment, and prepared the novel bioisosteric thiocytisine by oxygen-sulphur exchange. The affinities of these pyridone-modified analogs of (-)-cytisine for (alpha 4)(2)(beta 2)(3) and alpha 7* nAChRs in rat forebrain membranes were determined by competition with (+/-)-[(3)H]epibatidine and [(3)H]MLA, respectively. The 3-halocytisines 7 possess subnanomolar affinities for (alpha 4)(2)(beta 2)(3) nAChRs, higher than those found for (-)-cytisine as well as for the 5-halocytisines 8 and 3,5-dihalocytisines 6. In contrast to the parent alkaloid the 3-halogenated species display much a higher affinity for the alpha 7* nAChR subtype. The most potent molecule was 3-bromocytisine (7b) with preferential selectivity (200-fold) for the (alpha 4)(2)(beta 2)(3) subtype [K(i)=10 pM (alpha 4 beta 2) and 2.0 nM (alpha 7*)]. Replacement of the lactam with a thiolactam pharmacophore to thiocytisine (12) resulted in a subnanomolar affinity for the (alpha 4)(2)(beta 2)(3) nAChR subtype (K(i)=0.832 nM), but in a drastic decrease of affinity for the alpha 7* subtype; thiocytisine (12) has a K(i) value of 4000 nM (alpha 7*), giving a selectivity of 4800-fold for the neuronal (alpha 4)(2)(beta 2)(3)-nAChR and thus displaying the best affinity-selectivity profile in the series under consideration.
Imming
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Department of Pharmaceutical Chemistry, Philipps-University, Marbacher Weg 6, D-35032 Marburg, Germany.
Klaperski
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Stubbs
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MT
Seitz
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Gündisch
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D
D000157:Aconitine / Q000031:analogs & derivatives* / Q000378:metabolism; D000470:Alkaloids / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D001392:Azocines; D001667:Binding, Competitive; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000378:metabolism; D001952:Bridged-Ring Compounds / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D004353:Drug Evaluation, Preclinical / Q000379:methods; D006219:Halogens / Q000737:chemistry; D008024:Ligands; D018722:Nicotinic Agonists / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D011725:Pyridines / Q000378:metabolism; D011807:Quinolizines; D051381:Rats; D017207:Rats, Sprague-Dawley; D011978:Receptors, Nicotinic / Q000187:drug effects / Q000378:metabolism*; D013329:Structure-Activity Relationship; D000093843:Quinolizidine Alkaloids
D000157:Aconitine; D000470:Alkaloids; D001392:Azocines; D019086:Bridged Bicyclo Compounds, Heterocyclic; D001952:Bridged-Ring Compounds; D006219:Halogens; D008024:Ligands; D018722:Nicotinic Agonists; D011725:Pyridines; D011807:Quinolizines; D011978:Receptors, Nicotinic; C438730:3-bromocytisine; D000093843:Quinolizidine Alkaloids; C054634:methyllycaconitine; C004712:cytisine; C082748:epibatidine