Targeting Reward-Relevant Nicotinic Receptors in the Discovery of Novel Pharmacotherapeutic Agents to Treat Tobacco Dependence

Dwoskin, Linda P.; Pivavarchyk, Marharyta; Joyce, B. Matthew; Neugebauer, Nichole M.; Zheng, Guangrong; Zhang, Zhenfa; Bardo, Michael T.; Crooks, Peter A.

doi:10.1007/978-0-387-78748-0_4

Cited by 11 publications

(19 citation statements)

References 138 publications

(181 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Bupropion has also been shown to act as an antagonist at human α3β4 ganglionic nAChRs via an allosteric inhibitory mechanism (Fryer & Lukas, 1999) and inhibits α3β2, α4β2, and α7 nAChRs expressed in Xenopus oocytes (Slemmer, Martin, & Damaj, 2000). These studies indicate that bupropion-induced decreases in smoking likely result from both its nAChR antagonism and its DAT and NET inhibition properties (Dwoskin, Pivavarchyk, et al, 2009; Dwoskin, Smith, et al, 2009). The clinical effectiveness of bupropion as a smoking cessation agent has been evaluated (Wu, Wilson, Dimoulas, & Mills, 2006).…”

Section: Current Smoking Cessation Therapies That Target Nachrsmentioning

confidence: 95%

“…The α6-selective antagonist, α-conotoxin MII (α-CtxMII), also inhibits sazetidine A-evoked DA release ( I max = 50%). Sazetidine A substitutes completely for nicotine in drug discrimination studies in the rat and appears to act as a partial agonist at nAChRs in hippocampus and as a full agonist at nAChRs in striatum (Dwoskin, Pivavarchyk, et al, 2009; Dwoskin, Smith, et al, 2009; Xiao, Woolverton, Sahibzada, Yasuda, & Kellar, 2007). …”

Section: Emerging Potential Therapeutics For Treatment Of Tobacco mentioning

confidence: 99%

“…Reviews of our work on the discovery and development of bis-, tris-, and tetrakis-quaternary ammonium salts as potential smoking cessation agents provide a comprehensive account of how new leads from this drug discovery effort were developed in our preclinical pharmacological and behavioral evaluation programs (Dwoskin, Pivavarchyk, et al, 2009; Dwoskin, Smith, et al, 2009). …”

Section: Monoquaternary Ammonium Salts Derived From N-methylnicotimentioning

confidence: 99%

“…A published review (Dwoskin, Pivavarchyk, et al, 2009) provides additional information on the preclinical development of both bPiDDB and reduced bPiDDB (r-bPiDDB or bis-THP3) as nicotinic receptor-based therapeutics and candidates for smoking cessation. Both bPiDDB and bis-THP3 (Fig.…”

Section: Monoquaternary Ammonium Salts Derived From N-methylnicotimentioning

confidence: 99%

See 3 more Smart Citations

Nicotinic Receptor Antagonists as Treatments for Nicotine Abuse

Crooks

Bardo

Dwoskin

2014

Advances in Pharmacology

Self Cite

View full text Add to dashboard Cite

Despite the proven efficacy of current pharmacotherapies for tobacco dependence, relapse rates continue to be high, indicating that novel medications are needed. Currently, several smoking cessation agents are available, including varenicline (Chantix®), bupropion (Zyban®), and cytisine (Tabex®). Varenicline and cytisine are partial agonists at the α4β2* nicotinic acetylcholine receptor (nAChR). Bupropion is an antidepressant but is also an antagonist at α3β2* ganglionic nAChRs. The rewarding effects of nicotine are mediated, in part, by nicotine-evoked dopamine (DA) release leading to sensitization, which is associated with repeated nicotine administration and nicotine addiction. Receptor antagonists that selectivity target central nAChR subtypes mediating nicotine-evoked DA release should have efficacy as tobacco use cessation agents with the therapeutic advantage of a limited side-effect profile. While α-conotoxin MII (α-CtxMII)-insensitive nAChRs (e.g., α4β2*) contribute to nicotine-evoked DA release, these nAChRs are widely distributed in the brain, and inhibition of these receptors may lead to nonselective and untoward effects. In contrast, α-CtxMII-sensitive nAChRs mediating nicotine-evoked DA release offer an advantage as targets for smoking cessation, due to their more restricted localization primarily to dopaminergic neurons. Small drug-like molecules that are selective antagonists at α-CtxMII-sensitive nAChR subtypes that contain α6 and β2 subunits have now been identified. Early research identified a variety of quaternary ammonium analogs that were potent and selective antagonists at nAChRs mediating nicotine-evoked DA release. More recent data have shown that novel, non-quaternary bis-1,2,5,6-tetrahydropyridine analogs potently inhibit (IC50<1 nM) nicotine-evoked DA release in vitro by acting as antagonists at α-CtxMII-sensitive nAChR subtypes; these compounds also decrease NIC self-administration in rats.

show abstract

Section: Current Smoking Cessation Therapies That Target Nachrsmentioning

confidence: 95%

Section: Emerging Potential Therapeutics For Treatment Of Tobacco mentioning

confidence: 99%

Section: Monoquaternary Ammonium Salts Derived From N-methylnicotimentioning

confidence: 99%

Section: Monoquaternary Ammonium Salts Derived From N-methylnicotimentioning

confidence: 99%

See 2 more Smart Citations

Nicotinic Receptor Antagonists as Treatments for Nicotine Abuse

Crooks

Bardo

Dwoskin

2014

Advances in Pharmacology

Self Cite

View full text Add to dashboard Cite

show abstract

“…nAChR subtype diversity in function and pharmacological response are attributed to the specific subunit compositions, including α2-α10 and β2-β4 subunits encoded by individual subunit genes [16]. β2-Containing nAChRs mediate nicotine reward that results from presynaptic DA release following activation of α-conotoxin MII-sensitive nAChRs including α6β2β3*, α4α6β2β3*, α6β2* subtypes and α-conotoxin MII-insensitive α4β2* and α4α5β2* subtypes [17-20].…”

Section: Introductionmentioning

confidence: 99%

Angiotensin AT1 and AT2 receptor antagonists modulate nicotine-evoked [3H]dopamine and [3H]norepinephrine release

Narayanaswami¹,

Somkuwar²,

Horton³

et al. 2013

Biochemical Pharmacology

Self Cite

View full text Add to dashboard Cite

Tobacco smoking is the leading preventable cause of death in the United States. A major negative health consequence of chronic smoking is hypertension. Untoward addictive and cardiovascular sequelae associated with chronic smoking are mediated by nicotine-induced activation of nicotinic receptors (nAChRs) within striatal dopaminergic and hypothalamic noradrenergic systems. Hypertension involves both brain and peripheral angiotensin systems. Activation of angiotensin type-1 receptors (AT1) release dopamine and norepinephrine. The current study determined the role of AT1 and angiotensin type-2 (AT2) receptors in mediating nicotine-evoked dopamine and norepinephrine release from striatal and hypothalamic slices, respectively. The potential involvement of nAChRs in mediating effects of AT1 antagonist losartan and AT2 antagonist, 1-[[4-(dimethylamino)-3-methylphenyl]methyl]-5-(diphenylacetyl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-6-carboxylic acid (PD123319) was evaluated by determining their affinities for α4β2* and α7* nAChRs using [3H]nicotine and [3H]methyllycaconitine binding assays, respectively. Results show that losartan concentration-dependently inhibited nicotine-evoked [3H]dopamine and [3H]norepinephrine release (IC50: 3.9±1.2 and 2.2±0.7 μM; Imax: 82±3 and 89±6%, respectively). In contrast, PD123319 did not alter nicotine-evoked norepinephrine release, and potentiated nicotine-evoked dopamine release. These results indicate that AT1 receptors modulate nicotine-evoked striatal dopamine and hypothalamic norepinephrine release. Furthermore, AT1 receptor activation appears to be counteracted by AT2 receptor activation in striatum. Losartan and PD123319 did not inhibit [3H]nicotine or [3H]methyllycaconitine binding, indicating that these AT1 and AT2 antagonists do not interact with the agonist recognition sites on α4β2* and α7* nAChRs to mediate these effects of nicotine. Thus, angiotensin receptors contribute to the effects of nicotine on dopamine and norepinephrine release in brain regions involved in nicotine reward and hypertension.

show abstract