Yohannes D

References (8)

Title : Anticholinergic therapy for overactive bladder: a nicotinic modality? - Toler_2013_Med.Hypotheses_81_456
Author(s) : Toler SM , Yohannes D , Lippiello PM , Chancellor MB
Ref : Med Hypotheses , 81 :456 , 2013
Abstract : Until recently the treatment of Overactive Bladder (OAB) has primarily been aimed at mitigating hypercholinergic activity in the bladder via antagonism of muscarinic acetylcholine receptors. However, antimuscarinic therapies have limited efficacy and significant side effects. It is now known that nicotinic acetylcholine receptor (nAChR) subtypes are expressed in the urothelium and on afferent nerve fibers in the bladder, and it is believed that these receptors serve to communicate urgency and facilitate voiding function. This presents the opportunity for an alternative to the antimuscarinic approach, one which involves inhibition of nAChRs in the bladder that are chronically overstimulated by acetylcholine. Specifically, we hypothesize that an orally administered nAChR-selective inhibitor with extensive renal elimination will result in higher local concentrations in the bladder and lower systemic exposure than current therapies, representing a novel targeted approach to the treatment of OAB with a more favorable side effect profile.
ESTHER : Toler_2013_Med.Hypotheses_81_456
PubMedSearch : Toler_2013_Med.Hypotheses_81_456
PubMedID: 23834857

Title : Comparison of acetylcholine receptor interactions of the marine toxins, 13-desmethylspirolide C and gymnodimine - Hauser_2012_Neuropharmacol_62_2239
Author(s) : Hauser TA , Hepler CD , Kombo DC , Grinevich VP , Kiser MN , Hooker DN , Zhang J , Mountfort D , Selwood A , Akireddy SR , Letchworth SR , Yohannes D
Ref : Neuropharmacology , 62 :2239 , 2012
Abstract : The interaction of 13-desmethylspirolide C (SPX-desMe-C) and gymnodimine with several nicotinic and muscarinic acetylcholine receptors was investigated. Interaction at the muscarinic receptors was minimal. At nicotinic receptors, both SPX-desMe-C and gymnodimine displayed greatest affinity for the alpha7 receptor. The rank order for binding affinity (Ki) for SPX-desMe-C was alpha7 > alpha6beta3beta4alpha5 >> rat alpha3beta4, alpha1betagammadelta > alpha4beta4, human alpha3beta4 > human alpha4beta2 > rat alpha4beta2 and for gymnodimine was alpha7, alpha6beta3beta4alpha5 > rat alpha3beta4 > human alpha3beta4, alpha4beta4 > rat alpha4beta2, human alpha4beta2 > alpha1betagammadelta. Both molecules antagonized agonist-induced nicotinic responses. The antagonism rank order of potency (IC(50)) for SPX-desMe-C was alpha7 > low sensitivity (LS) alpha4beta2 > human alpha3beta4 > high sensitivity (HS) alpha4beta2, alpha1betagammadelta > alpha4beta4 > rat alpha3beta4 and for gymnodimine was LS alpha4beta2 > human alpha3beta4 > alpha7 > HS alpha4beta2 > alpha4beta4 > rat alpha3beta4 > alpha1betagammadelta. Neither gymnodimine nor SPX-desMe-C antagonism could be surmounted by increasing concentrations of nicotine. To elucidate the nature of this insurmountable blockade, we carried out homology modelling and molecular docking studies of both ligands with alpha7 nAChR. Their very high binding affinity results from very tight hydrophobic enclosures, in addition to previously reported hydrogen-bond and cation-pi interactions. Also, the higher the hydrophilic surface area of the binding site of nAChRs, the weaker the binding affinity of both ligands. Together these results show the targets of action are nicotinic and define these marine toxins as additional tools to advance our understanding regarding interactions between antagonists and the nAChR ligand binding domain.
ESTHER : Hauser_2012_Neuropharmacol_62_2239
PubMedSearch : Hauser_2012_Neuropharmacol_62_2239
PubMedID: 22306792

Title : Poster: Comparison of binding and functional activity profiles for a set of nicotinic acetylcholine receptor ligands across multiple alpha6* expression systems -
Author(s) : Breining SR , Hepler C , Whiteaker P , Quik M , Grady SR , Yohannes D
Ref : Biochemical Pharmacology , 82 :1024 , 2011

Title : Poster: Ligand-based QSAR modeling of neuronal nicotinic receptor data and its impact on drug design -
Author(s) : Hammond PS , Xiao Y-D , Kombo DC , Yohannes D
Ref : Biochemical Pharmacology , 82 :1027 , 2011

Title : Docking studies of benzylidene anabaseine interactions with alpha7 nicotinic acetylcholine receptor (nAChR) and acetylcholine binding proteins (AChBPs): application to the design of related alpha7 selective ligands - Kombo_2011_Eur.J.Med.Chem_46_5625
Author(s) : Kombo DC , Mazurov A , Tallapragada K , Hammond PS , Chewning J , Hauser TA , Vasquez-Valdivieso M , Yohannes D , Talley TT , Taylor P , Caldwell WS
Ref : Eur Journal of Medicinal Chemistry , 46 :5625 , 2011
Abstract : AChBPs isolated from Lymnaea stagnalis (Ls), Aplysia californica (Ac) and Bulinus truncatus (Bt) have been extensively used as structural prototypes to understand the molecular mechanisms that underlie ligand-interactions with nAChRs [1]. Here, we describe docking studies on interactions of benzylidene anabaseine analogs with AChBPs and alpha7 nAChR. Results reveal that docking of these compounds using Glide software accurately reproduces experimentally-observed binding modes of DMXBA and of its active metabolite, in the binding pocket of Ac. In addition to the well-known nicotinic pharmacophore (positive charge, hydrogen-bond acceptor, and hydrophobic aromatic groups), a hydrogen-bond donor feature contributes to binding of these compounds to Ac, Bt, and the alpha7 nAChR. This is consistent with benzylidene anabaseine analogs with OH and NH(2) functional groups showing the highest binding affinity of these congeners, and the position of the ligand shown in previous X-ray crystallographic studies of ligand-Ac complexes. In the predicted ligand-Ls complex, by contrast, the ligand OH group acts as hydrogen-bond acceptor. We have applied our structural findings to optimizing the design of novel spirodiazepine and spiroimidazoline quinuclidine series. Binding and functional studies revealed that these hydrogen-bond donor containing compounds exhibit improved affinity and selectivity for the alpha7 nAChR subtype and demonstrate partial agonism. The gain in affinity is also due to conformational restriction, tighter hydrophobic enclosures, and stronger cation-pi interactions. The use of AChBPs structure as a surrogate to predict binding affinity to alpha7 nAChR has also been investigated. On the whole, we found that molecular docking into Ls binding site generally scores better than when a alpha7 homology model, Bt or Ac crystal structure is used.
ESTHER : Kombo_2011_Eur.J.Med.Chem_46_5625
PubMedSearch : Kombo_2011_Eur.J.Med.Chem_46_5625
PubMedID: 21986237

Title : Structural differences determine the relative selectivity of nicotinic compounds for native alpha 4 beta 2*-, alpha 6 beta 2*-, alpha 3 beta 4*- and alpha 7-nicotine acetylcholine receptors - Grady_2010_Neuropharmacol_58_1054
Author(s) : Grady SR , Drenan RM , Breining SR , Yohannes D , Wageman CR , Fedorov NB , McKinney S , Whiteaker P , Bencherif M , Lester HA , Marks MJ
Ref : Neuropharmacology , 58 :1054 , 2010
Abstract : Mammalian brain expresses multiple nicotinic acetylcholine receptor (nAChR) subtypes that differ in subunit composition, sites of expression and pharmacological and functional properties. Among known subtypes of receptors, alpha 4 beta 2* and alpha 6 beta 2*-nAChR have the highest affinity for nicotine (where * indicates possibility of other subunits). The alpha 4 beta 2*-nAChRs are widely distributed, while alpha 6 beta 2*-nAChR are restricted to a few regions. Both subtypes modulate release of dopamine from the dopaminergic neurons of the mesoaccumbens pathway thought to be essential for reward and addiction. alpha 4 beta 2*-nAChR also modulate GABA release in these areas. Identification of selective compounds would facilitate study of nAChR subtypes. An improved understanding of the role of nAChR subtypes may help in developing more effective smoking cessation aids with fewer side effects than current therapeutics. We have screened a series of nicotinic compounds that vary in the distance between the pyridine and the cationic center, in steric bulk, and in flexibility of the molecule. These compounds were screened using membrane binding and synaptosomal function assays, or recordings from GH4C1 cells expressing h alpha 7, to determine affinity, potency and efficacy at four subtypes of nAChRs found in brain, alpha 4 beta 2*, alpha 6 beta 2*, alpha 7 and alpha 3 beta 4*. In addition, physiological assays in gain-of-function mutant mice were used to assess in vivo activity at alpha 4 beta 2* and alpha 6 beta 2*-nAChRs. This approach has identified several compounds with agonist or partial agonist activity that display improved selectivity for alpha 6 beta 2*-nAChR.
ESTHER : Grady_2010_Neuropharmacol_58_1054
PubMedSearch : Grady_2010_Neuropharmacol_58_1054
PubMedID: 20114055

Title : Evaluation of structurally diverse neuronal nicotinic receptor ligands for selectivity at the alpha6( *) subtype - Breining_2009_Bioorg.Med.Chem.Lett_19_4359
Author(s) : Breining SR , Bencherif M , Grady SR , Whiteaker P , Marks MJ , Wageman CR , Lester HA , Yohannes D
Ref : Bioorganic & Medicinal Chemistry Lett , 19 :4359 , 2009
Abstract : Direct comparison of pyridine versus pyrimidine substituents on a small but diverse set of ligands indicates that the pyrimidine substitution has the potential to enhance affinity and/or functional activity at alpha6 subunit-containing neuronal nicotinic receptors (NNRs) and decrease activation of ganglionic nicotinic receptors, depending on the scaffold. The ramifications of this structure-activity relationship are discussed in the context of the design of small molecules targeting smoking cessation.
ESTHER : Breining_2009_Bioorg.Med.Chem.Lett_19_4359
PubMedSearch : Breining_2009_Bioorg.Med.Chem.Lett_19_4359
PubMedID: 19560354

Title : Poster: Discovery of a novel, structurally unique class of muscarinic agonists -
Author(s) : Ward KM , Hubbard ST , Jones SB , Nason DM , Lee MH , Biggers CK , Nowakowski J , Yohannes D , Villalobos A , Snider RM , White WF , Liston DR
Ref : Life Sciences , 60 :1164 , 1997