Natural Sympathomimetic Drugs: From Pharmacology to Toxicology

Abstract

Sympathomimetic agents are a group of chemical compounds that are able to activate the sympathetic nervous system either directly via adrenergic receptors or indirectly by increasing endogenous catecholamine levels or mimicking their intracellular signaling pathways. Compounds from this group, both used therapeutically or abused, comprise endogenous catecholamines (such as adrenaline and noradrenaline), synthetic amines (e.g., isoproterenol and dobutamine), trace amines (e.g., tyramine, tryptamine, histamine and octopamine), illicit drugs (e.g., ephedrine, cathinone, and cocaine), or even caffeine and synephrine. In addition to the effects triggered by stimulation of the sympathetic system, the discovery of trace amine associated receptors (TAARs) in humans brought new insights about their sympathomimetic pharmacology and toxicology. Although synthetic sympathomimetic agents are mostly seen as toxic, natural sympathomimetic agents are considered more complacently in the terms of safety in the vision of the lay public. Here, we aim to discuss the pharmacological and mainly toxicological aspects related to sympathomimetic natural agents, in particular of trace amines, compounds derived from plants like ephedra and khat, and finally cocaine. The main purpose of this review is to give a scientific and updated view of those agents and serve as a reminder on the safety issues of natural sympathomimetic agents most used in the community.

Keywords: adrenaline; cathinone; cocaine; ephedrine; trace amines.

Figure 1

Chemical structure of biogenic catecholamines (dopamine, adrenaline and noradrenaline) and their parent chemical structure (β-phenylethylamine).

Figure 2

Chemical structures of several natural occurring sympathomimetics.

Figure 3

Trace amines activate TAAR1, leading to adenylyl cyclase (AC) activation and downstream activation of protein kinase A and protein kinase C. Interactions with the dopaminergic system can also occur and TAAR1 may translocate to the cell surface after heterodimerization with dopamine receptor 2 (D2), an effect that promotes preferential signaling related to dopamine and through the Gi signal transduction cascade, while blocking the β-arrestin 2 pathway. In addition, K+ channels can be activated in the presence of TAAR agonists. Figure built resourcing to the blocks of Servier Medical Art.

Figure 4

Interactions on the synaptic cleft of several sympathomimetics. Figure built resourcing to the blocks of Servier Medical Art.