(""""""""Ecstasy"""""""") is a popular drug of abuse especially among youth in the population. Use of MDMA is associated with acute physiological effects (e.g. hyperthermia) which may lead to serious organ damage. MDMA is neurotoxic and cognitive and psychological deficits have been noted in consumers of the drug. Furthermore, some individuals meet the criteria for dependence on MDMA. There is currently an unmet medical need for a therapeutic agent to combat MDMA overdose and abuse. Blockade of serotonin 5-HT2A and 11A adrenergic receptors have been shown to antagonize a range of MDMA- induced behavioral and physiological effects in animal models. The goal of this project is to elucidate structural features of our lead molecule nantenine that are required for antagonism of 5-HT2A and 11A adrenergic receptors. We will test the central hypothesis that structural modifications of nantenine will yield novel 5-HT2A antagonists and novel 11A adrenoceptor antagonists. To test this hypothesis we will engage a structure-activity relationship (SAR) study involving three specific aims. In the first specific aim, we will examine the effects of replacement of substituents on ring A of nantenine on antagonizing the targeted receptors. For the second specific aim, the pharmacophoric relevance of the methylenedioxyphenyl ring of nantenine will be evaluated through the synthesis of novel heterocyclic derivatives.
In specific aim 3, the importance of the N-substituent group will be analyzed. Selected compounds will be advanced to behavioral assays in rodents in order to characterize their pharmacological profiles as potential MDMA antagonists.
|Marchant, Jonathan S; Harding, Wayne W; Chan, John D (2018) Structure-activity profiling of alkaloid natural product pharmacophores against a Schistosoma serotonin receptor. Int J Parasitol Drugs Drug Resist 8:550-558|
|Manuszak, M; Harding, W; Gadhiya, S et al. (2018) (-)-Stepholidine reduces cue-induced reinstatement of cocaine seeking and cocaine self-administration in rats. Drug Alcohol Depend 189:49-54|
|Madapa, Sudharshan; Gadhiya, Satishkumar; Kurtzman, Thomas et al. (2017) Synthesis and evaluation of C9 alkoxy analogues of (-)-stepholidine as dopamine receptor ligands. Eur J Med Chem 125:255-268|
|Kapadia, Nirav; Ahmed, Shahrear; Harding, Wayne W (2016) New halogenated tris-(phenylalkyl)amines as h5-HT2B receptor ligands. Bioorg Med Chem Lett 26:3216-3219|
|Gadhiya, Satishkumar; Madapa, Sudharshan; Kurtzman, Thomas et al. (2016) Tetrahydroprotoberberine alkaloids with dopamine and ? receptor affinity. Bioorg Med Chem 24:2060-71|
|Gadhiya, Satishkumar V; Hu, Chunhua; Harding, Wayne W (2016) An alternative synthesis and x-ray crystallographic confirmation of (-)-stepholidine. Tetrahedron Lett 57:2090-2092|
|Madapa, Sudharshan; Harding, Wayne W (2015) Semisynthetic Studies on and Biological Evaluation of N-Methyllaurotetanine Analogues as Ligands for 5-HT Receptors. J Nat Prod 78:722-9|
|Ponnala, Shashikanth; Kapadia, Nirav; Madapa, Sudharshan et al. (2015) Synthesis and evaluation of aporphine analogs containing C1 allyl isosteres at the h5-HT(2A) receptor. Bioorg Med Chem Lett 25:5102-6|
|Gadhiya, Satish; Ponnala, Shashikanth; Harding, Wayne W (2015) A divergent route to 9, 10-oxygenated tetrahydroprotoberberine and 8-oxoprotoberberine alkaloids: synthesis of (±)-isocorypalmine and oxypalmatine. Tetrahedron 71:1227-1231|
|Kapadia, Nirav; Harding, Wayne W (2015) C4 phenyl aporphines with selective h5-HT(2B) receptor affinity. Bioorg Med Chem Lett 25:3451-4|
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