Binding monoamine antagonists

Monoamine Antagonists Often Bind Close to Where the Agonist Binds... 

While the agonist binding domain is thought to be within the transmembrane domains for the monoamine and nucleotide receptors, neuropeptides are thought to bind close to the membrane surface on the extracellular domains of the receptor. It is still not clear whether non-peptide antagonists bind at the same or a different site on the receptor. 

Wiley JL, LaVecchia KL, Martin BR, Damaj MI (2002) Nicotine-like discriminative stimulus effects of bupropion in rats. Exp Clin Psychopharmacol 10 129-135 Williams M, Robinson JL (1984) Binding of the nicotinic cholinergic antagonist, dihydro-beta-erythroidine, to rat brain tissue. J Neurosci 4 2906-2911 Witkin JM, Dykstra LA, Carter RB (1982) Acute tolerance to the discriminative stimulus properties of morphine. Pharmacol Biochem Behav 17 223-228 Wooters TE, Bardo MT (2007) The monoamine oxidase inhibitor phenelzine enhances the discriminative stimulus effect of nicotine in rats. Behav Pharmacol 18 601-608 Wright JM Jr, Vann RE, Gamage TE, Damaj MI, WUey JL (2006) Comparative effects of dextromethorphan and dextrorphan on nicotine discrimination in rats. Pharmacol Biochem Behav 85 507-513... 

As previously noted, all currently available antidepressants enhance monoamine neurotransmission by one of several mechanisms. The most common mechanism is inhibition of the activity of SERT, NET, or both monoamine transporters (Table 30-2). Antidepressants that inhibit SERT, NET, or both include the SSRIs and SNRIs (by definition), and the TCAs. Another mechanism for increasing the availability of monoamines is inhibition of their enzymatic degradation (the MAOIs). Additional strategies for enhancing monoamine tone include binding presynaptic autoreceptors (mirtazapine) or specific postsynaptic receptors (5-HT antagonists and mirtazapine). Ultimately, the increased availability of monoamines for... 

Considerable attention has been paid to the ultimate postsynaptic effects of increased neurotransmitters in the synapses. In tests of postsynaptic effects, cAMP concentrations have consistently decreased rather than increased, in spite of the presumably longer duration of action of the transmitters. In addition, the number of postsynaptic -adrenoceptors has shown a measurable decrease that follows the same delayed time course as clinical improvement in patients. Thus, the initial increase in neurotransmitter seen with some antidepressants appears to produce, over time, a compensatory decrease in receptor activity, ie, down-regulation of receptors. Decreases in norepinephrine-stimulated cAMP and in B-adrenoceptor binding have been conclusively shown for selective norepinephrine uptake inhibitors, those with mixed action on norepinephrine and serotonin, monoamine oxidase inhibitors, and even electroconvulsive therapy. Such changes do not consistently occur after the selective serotonin uptake inhibitors, 2 receptor antagonists, and mixed serotonin antagonists. 

Lobeline is derived from the plant Lobelia inflata (Indian tobacco). It is both an agonist and an antagonist at nicotinic receptors, although it is not structurally related to nicotine (1). It inhibits nicotine- and amphetamine-induced dopamine release by interacting with the tetra-benazine-binding site on the monoamine transporter. It also inhibits dopamine re-uptake. It has been used in smoking cessation, but is ineffective (2). 

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