Atropine-type compounds

Dicyclomine hydrochloride has one eighth of the neii-rotropic activity of atropine and approximately twice the musculotropic activity of papaverine. This preparation. liN introduced in 1950. has minimized the adverse effects asso. dated with the atropine-type compounds. It is used for its spasmolytic effect on variou.s smtxrth muscle spa.snts. particularly those associated with the GI tract. It is also useful in dysmenorrhea. pylorospa.sm. and biliary dysfunction. 

It possesses approximately l/8th the neurotropic activity of atropine, and nearly double the musculotropic activity of papaverine. It has substantially minimised the imdesirable side effect intimately linked with the atropine-type compounds. It exerts its spasmolytic effect on various smooth-muscle spasms, specifically those associated with the Gl-tract. 

The work with atropine presents a confusing picture. Use of racemic radioligand in these studies may contribute to the observed cross-reactivity picture. The rather facile enolization and hence racemization of atropine-type structures is another problem. FinaUy, the structure of the product of atropine and diazotized p-aminobenzoic acid has never been established conclusively. For these reasons, the radioreceptor assay for this compound (see below) is generally preferable. 

Natural tropane type compounds causing such effects are hyoscyamine/atropine, 6(3-hydroxyhyoscyamine (anisodamine), anisodine, and scopolamine. They are still today important drugs (Liu et al. 2005) though their semisynthetic derivatives are meanwhile even more important. Traditionally they were called parasympatholytics. Nowadays, they are termed competitive inhibitors (of all known types) of muscarinic acetylcholine receptors (for details see Sect. 3.3.6). As SchmeUer et al. (2000) could demonstrate, such tropane alkaloids do not interfere only with these types of neuroceptors but also bind to the nicotinic ones albeit with much lower affinities. This was determined not only for atropine and scopolamine but also with similar affinities for their intermediates/congeners littorine, 6P- and P-hydroxy-hyoscyamine. However, semisynthetic quaternary compounds like the A/-methyl derivatives of atropine and scopolamine were found to show the highest binding. 

Neutral loss Neutral loss monitoring allows the detection of any compound that loses a specified mass during CID. This scan type allowed to detect any glucuronides (neutral loss of 176 Da), sulpho-conjugates (loss of 80 Da) and was helpful to identify molecules that lose a tropic acid moiety (loss of 166 Da) or a tropic acid-derived HCOH group (loss of 30 Da) [51, 52], The occurrence of the latter losses provided helpful hints for the presence of an (partly) unaltered tropic acid moiety in, e.g. atropine. 

Most of the experimental chemicals were administered to too few volunteers to be examined separately for an influence on mortality. However, a few were considered of sufficient interest to justify being examined in that way (Table 4-4). The specific chemicals are grouped by type. The SMRs for these individual compounds range from a low of 0.80 (nine observed, 11.3 expected deaths) for the men rested with sarin only, to a high of 2.50 (five observed, two expected) for scopolamine only. Atropine, a therapeutic anticholinergic similar to scopolamine, had the next highest SMR, 1 76 (three observed, 1.7 expected). Of the eight deaths of men who received one or the other of these two therapeutically similar compounds, three were attributed to trauma (one accident, one suicide, and one other trauma), and one was due to cancer the causes of the other four will not be known until the death certificates are obtained. 

Aaltonen et al. (61) compared RRA and RIA for atropine. These workers obtained preparations of receptor from rat brain and lyophilized them to a stable, dry form, They used the tritium-labeled quinuclidinyl benzilate at 35 Ci/mmol. The affinity constant was 0.48 nM, and by analysis of 25- xL serum samples they could obtain a sensitivity down to 1.25 ng/mL in serum. Nonspecific binding was again quite reasonable (4%) and a filtration-type separation was used. The d isomer of an atropine did not bind, and therefore, the cross-reaction of the d,l compound was 50% that of the ( isomer. For comparison they used RIA developed by the method of Virtanen et al, (37). The immunogen was an /-hyoscyamine-bovine serum albumin conjugate, but the antiserum was sensitive to both d,l and I isomers. Racemic tritium-labeled atropine was used as the radioligand. 

The effect of various mobile-phase modifiers on a is the result of a highly complex relationship involving the structure of the solute, as well as the structure and type of modifier, and may also involve changes in the conformation of the AGP (95). The complexity of this relationship is illustrated by the effect of various modifiers on the chiral resolution of two closely related compounds, atropine and N-methylhomatropine (Fig. 13). 

For their antispasmodic and antisecretory activities in humans, the drugs are administered orally. A comparison of their oral doses (micromoles) indicates that atropine is the most active compound. In clinical experience all three types of anticholinergic activities are exhibited by all compounds. The principal advantage of the available quaternary ammonium compounds lies in the fact that they are elatively free of any of the CNS effects that rm/ be seen with atropine. This may permit the administration of sufficient quantities of the compounds to achieve a more fully effective peripheral anticholinergic action. 

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). 

The first is the u,sc of a suitable. sensitive species (usually Che adult hen), in which test substance is administered at two acute exposures (separated by 21 days) to atropine-protected animals at a level at or above the LD50 of the compound. Observations on body weight, ataxia, and signs of delayed neurotoxicity are made while the animals are alive. At termination, usually 42 days after the first dose, histopathological examination of the brain, spinal cord, and proximal and distal sections of (usually) the sciatic nerve is performed. Data from this type of test suffer from two major drawbacks The evaluation is often subjective, and a negative result cannot be graded,... 

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