title: Tricyclic antidepressants and mecamylamine bind to different sites in the human alpha4beta2 nicotinic receptor ion channel.
abstract: The interaction of tricyclic antidepressants with the human (h) alpha4beta2 nicotinic acetylcholine receptor in different conformational states was compared with that for the noncompetitive antagonist mecamylamine by using functional and structural approaches. The results established that: (a) [(3)H]imipramine binds to halpha4beta2 receptors with relatively high affinity (K(d)=0.83+/-0.08 microM), but imipramine does not differentiate between the desensitized and resting states, (b) although tricyclic antidepressants inhibit (+/-)-epibatidine-induced Ca(2+) influx in HEK293-halpha4beta2 cells with potencies that are in the same concentration range as that for (+/-)-mecamylamine, tricyclic antidepressants inhibit [(3)H]imipramine binding to halpha4beta2 receptors with affinities >100-fold higher than that for (+/-)-mecamylamine. This can be explained by our docking results where imipramine interacts with the leucine (position 9') and valine (position 13') rings by van der Waals contacts, whereas mecamylamine interacts electrostatically with the outer ring (position 20'), (c) van der Waals interactions are in agreement with the thermodynamic results, indicating that imipramine interacts with the desensitized and resting receptors by a combination of enthalpic and entropic components. However, the entropic component is more important in the desensitized state, suggesting local conformational changes. In conclusion, our data indicate that tricyclic antidepressants and mecamylamine efficiently inhibit the ion channel by interacting at different luminal sites. The high proportion of protonated mecamylamine calculated at physiological pH suggests that this drug can be attracted to the channel mouth before binding deeper within the receptor ion channel finally blocking ion flux.
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, Midwestern University, 19555 N 59th Avenue, Glendale, AZ 85308, USA. harias@midwestern.edu
authors.forename: Hugo R
authors.initials: HR
authors.lastname: Arias
authors.forename: Avraham
authors.initials: A
authors.lastname: Rosenberg
authors.forename: Katarzyna M
authors.initials: KM
authors.lastname: Targowska-Duda
authors.forename: Dominik
authors.initials: D
authors.lastname: Feuerbach
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Jozwiak
authors.forename: Ruin
authors.initials: R
authors.lastname: Moaddel
authors.forename: Irving W
authors.initials: IW
authors.lastname: Wainer
mesh_terms: D000929:Antidepressive Agents, Tricyclic / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D001665:Binding Sites; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D020013:Calcium Signaling / Q000187:drug effects; D002460:Cell Line; D006801:Humans; D007099:Imipramine / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D007473:Ion Channels / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D008464:Mecamylamine / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D018733:Nicotinic Antagonists / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D011485:Protein Binding; D011487:Protein Conformation / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology; D011978:Receptors, Nicotinic / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: D000929:Antidepressive Agents, Tricyclic; D019086:Bridged Bicyclo Compounds, Heterocyclic; D007473:Ion Channels; D018733:Nicotinic Antagonists; D011725:Pyridines; D011978:Receptors, Nicotinic; C403531:nicotinic receptor alpha4beta2; D008464:Mecamylamine; C082748:epibatidine; D007099:Imipramine