title: Introduction of unsaturation into the N-n-alkyl chain of the nicotinic receptor antagonists, NONI and NDNI: effect on affinity and selectivity.
abstract: N-n-octylnicotinium iodide (NONI) and N-n-decylnicotinium iodide (NDNI) are selective nicotinic receptor (nAChR) antagonists mediating nicotine-evoked striatal dopamine (DA) release, and inhibiting [3H]nicotine binding, respectively. This study evaluated effects of introducing unsaturation into the N-n-alkyl chains of NONI and NDNI on inhibition of [3H]nicotine and [3H]methyllycaconitine binding (alpha4beta2* and alpha7* nAChRs, respectively), (86)Rb+ efflux and [3H]DA release (agonist or antagonist effects at alpha4beta2* and alpha6beta2*-containing nAChRs, respectively). In the NONI series, introduction of a C3-cis- (NONB3c), C3-trans- (NONB3t), C7-double-bond (NONB7e), or C3-triple-bond (NONB3y) afforded a 4-fold to 250-fold increased affinity for [3H]nicotine binding sites compared with NONI. NONB7e and NONB3y inhibited nicotine-evoked 86Rb+ efflux, indicating alpha4beta2* antagonism. NONI analogs exhibited a 3-fold to 8-fold greater potency inhibiting nicotine-evoked [3H]DA overflow compared with NONI (IC50 = 0.62 microM; Imax = 89%), with no change in Imax, except for NONB3y (Imax = 50%). In the NDNI series, introduction of a C4-cis- (NDNB4c), C4-trans-double-bond (NDNB4t), or C3-triple-bond (NDNB3y) afforded a 4-fold to 80-fold decreased affinity for [3H]nicotine binding sites compared with NDNI, whereas introduction of a C9 double-bond (NDNB9e) did not alter affinity. NDNB3y and NDNB4t inhibited nicotine-evoked 86Rb+ efflux, indicating antagonism at alpha4beta2* nAChRs. Although NDNI had no effect, NDNB4t and NDNB9e potently inhibited nicotine-evoked [3H]DA overflow (IC50 = 0.02-0.14 microM, Imax = 90%), as did NDNB4c (IC50 = 0.08 microM; Imax = 50%), whereas NDNB3y showed no inhibition. None of the analogs had significant affinity for alpha7* nAChRs. Thus, unsaturated NONI analogs had enhanced affinity at alpha4beta2*- and alpha6beta2*-containing nAChRs, however a general reduction of affinity at alpha4beta2* and an uncovering of antagonist effects at alpha6beta2*-containing nAChRs were observed with unsaturated NDNI analogs.
authors.affiliation: College of Pharmacy, University of Kentucky, Lexington, KY 40536-0082, USA.
authors.forename: Sangeetha P
authors.initials: SP
authors.lastname: Sumithran
authors.forename: Peter A
authors.initials: PA
authors.lastname: Crooks
authors.forename: Rui
authors.initials: R
authors.lastname: Xu
authors.forename: Jun
authors.initials: J
authors.lastname: Zhu
authors.forename: Agripina G
authors.initials: AG
authors.lastname: Deaciuc
authors.forename: Lincoln H
authors.initials: LH
authors.lastname: Wilkins
authors.forename: Linda P
authors.initials: LP
authors.lastname: Dwoskin
mesh_terms: D000157:Aconitine / Q000031:analogs & derivatives / Q000378:metabolism; D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism*; D050483:Dopamine Plasma Membrane Transport Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D004558:Electric Stimulation; D006801:Humans; D008297:Male; D015394:Molecular Structure; D009538:Nicotine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D018733:Nicotinic Antagonists / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D009627:Nomifensine / Q000494:pharmacology; D011485:Protein Binding; D021122:Protein Subunits; D051381:Rats; D017207:Rats, Sprague-Dawley; D011978:Receptors, Nicotinic / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism; D012201:Reward; D012413:Rubidium / Q000032:analysis; D013329:Structure-Activity Relationship; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism
chemical_list: D050483:Dopamine Plasma Membrane Transport Proteins; C507707:N-(n-dec-9-enyl)nicotinium; C507706:N-(n-oct-3-enyl)nicotinium; C403088:N-n-decylnicotinium; C507705:N-n-octylnicotinium; D018733:Nicotinic Antagonists; D021122:Protein Subunits; D011978:Receptors, Nicotinic; C559463:alpha6beta2 nicotinic acetylcholine receptor; C403531:nicotinic receptor alpha4beta2; D009627:Nomifensine; C054634:methyllycaconitine; D009538:Nicotine; D012413:Rubidium; D004298:Dopamine; D000157:Aconitine