Atropine synthetic derivatives

Figure 1.13. Stractures of acetylcholine and its competitors atropine and ipratropium. Atropine occurs naturally in Atropa belladonna. Ipratropium is a synthetic derivative.

When one considers the therapeutic impact of morphine, quinine, digitalis, ergot, atropine, cocaine, reserpine, and vincaleukoblastine, to name but a few, it is evident how great is the debt of medicine to plant-derived drugs even today. If one adds the synthetic derivatives and variants of plant-derived products, the role of natural products from plant sources has been most impressive. 

The class of drugs referred to as muscarinic receptor antagonists includes (1) the naturally occurring alkaloids, atropine and scopolamine (2) semisynthetic derivatives of these alkaloids, which primarily differ from the parent compounds in their disposition in the body or their duration of action and (3) synthetic congeners, some of which show selectivity for particular subtypes of muscarinic receptors. Noteworthy agents among the synthetic derivatives are homatropine and tropicamide, which have a... 

The pronounced pharmacological activity associated with the tropine and scopine skeletons prompted the synthesis of a number of semi-synthetic derivatives of the solanaceous alkaloids in which various other acids were substituted for tropic acid [390]. Anticholinergic activity was evident in many of these synthetic atropine-like molecules, but only two, benztropin (Cogentin, Cobrentin, 7) and ethylbenzatropin (Ponalide, 8), have found clinical use in Parkinsonism. Neither the latter nor tigloidine (9), originally isolated from... 

The best known of the muscarinic blocking drugs are the belladonna alkaloids, atropine (Atropine) and scopolamine (Scopolamine). They are tertiary amines that contain an ester linkage. Atropine is a racemic mixture of DL-hyoscyamine, of which only the levorotatory isomer is pharmacologically active. Atropine and scopolamine are parent compounds for several semisynthetic derivatives, and some synthetic compounds with little structural similarity to the belladonna alkaloids are also in use. All of the antimuscarinic compounds are amino alcohol esters with a tertiary amine or quaternary ammonium group. 

During the late 1930s some 4-phenylpiperidine derivatives were examined as potential spasmolytics on the basis of their chemical relationship to atropine. The antinociceptive properties of one member, ethyl 1-methyl-4-phenyl-piperidine-4-carboxylate, was detected in screening tests and the compound was subsequently introduced into clinical use by Eisleb and Schaumann in 1939. The compound, well known as pethidine in Europe and meperidine in North America (proprietary names include Demerol, Dolantin, and Dolosal), was soon in widespread use for the relief of pain, and it is remarkable how pethidine, the original non-opioid-derived opioid analgesic, has retained its popularity for many years in the face of competition from other synthetic analgesics introduced since 1939. 

The alkaloids of this group are derived from a combination of a piperidine and a pyrrolidine ring, designated as tropane (Figure 14.2). The 3-hydroxy derivative of tropane is known as tropine and is the basic component of atropine. When atropine is hydrolyzed, it forms tropine and tropic acid (a-phenyl-p-hydroxy-propionic acid). Atropine is the tropic acid ester of tropine. It has been prepared synthetically. Tropic acid contains an asymmetric carbon atom. The racemic compound (atropine) as obtained naturally or as synthesized may be resolved into its optically active components, d- and /-hyoscyamine. Atropine is racemic hyoscyamine that is, it consists of equal parts of /-hyscyamine and plant cells and also in the process of extraction, so that the relative proportion of the isomers in the plants and in the preparations varies. However, atropine itself does exist in small amounts in the plants, although most of it is formed from the /-hyoscyamine in the process of extraction. 

The first name commemorates its success as a homicidal poison, for it is derived from the senior of three legendary Fates, Atropos, who cuts with shears the web of life spun and woven by her sisters Clothos and Lachesis (there is a minor synthetic atropine-like drug called lachesine). The term belladonna (Italian beautiful woman) refers to the once fashionable female practice of using an extract of the plant to dilate the pupils (incidentally blocking ocular accommodation) as part of the process of making herself attractive. 

As a class, anticholinergics include the antihistamines, atropine and homatropine anti-Parkinsonian agents like benzotropine, procyclidine, and trihexyphenidyl the antimuscarinics of which atropine is the prototype and antispasmodics like dicyclomine and oxybutymin. Most antimuscarinics are amino-alcohols or their derivatives (usually esters or ethers), aminoamides, or other amines. Antimuscarinics can be divided into two groups. These are the naturally occurring alkaloids and their semisynthetic derivatives like atropine, homatropine, scopolamine, and hyoscyamine and the synthetic amine compounds such as anisotropine, dicyclomine, and ipratropium. 

Methyl atropine nitrate (10)(or bromide) is a synthetic quaternary derivative of atropine. Atropine oxide (atropineN-oxide)is known as a genatropine (1 l)and may be prepared by oxidation of the alkaloid with hydrogen peroxide. 

In addition to modifications of the morphine molecule, many purely synthetic analgesics have been produced, the first of these, pethidine (meperidine), having been synthesized in 1939 in an attempt to make a substitute for atropine (276). As in the case of heroin, pethidine was at first thought to be nonaddictive. It has been followed by a hundred or so other compounds of several different types, but, as with the morphine derivatives, none, with the possible exception of pentazocine, has been found to have analgesic without addictive properties. However, it seems that the two effects may not be entirely inseparable, as diphenoxylate, which has come into use as an antidiarrheal drug, has been found to possess the power to cause addiction but no analgesic action at all (277). 

Intellectual, Synthetic Substitutes of Atropine. Atropine was used for many decades as a mydriatic in ophthalmologic diagnostics. The disadvantage of the alkaloid was the enduring irritation of the patients for hours (dilated pupils). Nowadays, ophthalmologists prefer, e.g., tropicamide whose name (INN) was created in memory of its natural precursor it represents an intellectual derivative of atropine with decisive, retained structural characters of the alkaloid (Fig. 3.25). 

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