Beauty of the beast: anticholinergic tropane alkaloids in therapeutics

Abstract

Tropane alkaloids (TAs) are among the most valued chemical compounds known since pre-historic times. Poisonous plants from Solanaceae family (Hyoscyamus niger, Datura, Atropa belladonna, Scopolia lurida, Mandragora officinarum, Duboisia) and Erythroxylaceae (Erythroxylum coca) are rich sources of tropane alkaloids. These compounds possess the anticholinergic properties as they could block the neurotransmitter acetylcholine action in the central and peripheral nervous system by binding at either muscarinic and/or nicotinic receptors. Hence, they are of great clinical importance and are used as antiemetics, anesthetics, antispasmodics, bronchodilator and mydriatics. They also serve as the lead compounds to generate more effective drugs. Due to the important pharmacological action they are listed in the WHO list of essential medicines and are available in market with FDA approval. However, being anticholinergic in action, TA medication are under the suspicion of causing dementia and cognitive decline like other medications with anticholinergic action, interestingly which is incorrect. There are published reviews on chemistry, biosynthesis, pharmacology, safety concerns, biotechnological aspects of TAs but the detailed information on anticholinergic mechanism of action, clinical pharmacology, FDA approval and anticholinergic burden is lacking. Hence the present review tries to fill this lacuna by critically summarizing and discussing the above mentioned aspects.

Keywords: Anticholinergic action; Anticholinergic burden; Muscarinic and nicotinic receptors; Poisonous plants; Therapeutics; Tropane alkaloids.

Fig. 1

Anticholinergic Action of Tropane Alkaloids. Tropane alkaloids are anticholinergic in action. TAs competitively bind to muscarinic and/or nicotinic receptors and block ACh transmission. MR: Muscarinic receptor; NR: Nicotinic receptor; ACh: Acetylcholine; PLC: Phospholipase C; AC: Adenylyl cyclase; MAPK: Mitogen-activated protein kinase [Prepared using Biorender.com]

Fig. 2

Structure of natural tropane alkaloids

Fig. 3

Biosynthetic pathway of tropane alkaloids

Fig. 4

Autonomic nervous system and location of receptors. Nerves of autonomic nervous system (ANS) extend from central nervous system (CNS) to cardiac muscle, smooth muscle, organs and glands by preganglionic (Pre GN) and postganglionic (Post GN) neurons. PreGN releases acetylcholine (ACh) into the synaptic cleft and get bind to nicotine receptors (NR) in Post GN. Depolarization of membrane results in action potential which on arriving at the axon terminal releases neurotransmitter: ACh, norepinephrine (NE) or epinephrine (EN) in the synaptic cleft. The binding of neurotransmitter to the receptors: Androgenic (AR) or muscarinic (M) on the target organ results in excitation or inhibition. (1–3) Sympathetic system, (4) Parasympathetic system. These two systems differ in the type of neurotransmitter released, type of receptors and secondary messengers expressed [Prepared using Biorender.com]

Fig. 5

Pharmaceutically important tropane alkaloid derivatives