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APPENDIX K BIOCHEMICAL ASPECTS OF ANTICHOLINERGIC CHEMICALS by John J. O'Nelll, Ph.D.* There have been few published studies--an example {a that by Jovic and Zupanc (l)--on the biochemical mechanisms associated with qulnuclitloyl benzllate (BZ). ~ major attribute of atropine, scopolamine, and other antlcholinerglc compounds is their ability to interact with poat~ynaptic muscarinic binding sites. It is through such an action on smooth muscle that our ideas about BZ ant other potent antlcholinergica have developed. A property common to all la a high affinity for muscarinic receptor sites IKE ~ 0.05 - O.l x 10-9 A). A regional study with t3~3BZ of binding capacity in hippocampus, frontal cortex. and caudate nucleus of human bests showed (2), small decreases in these areas in Bunti~gton's chores patients as compared with normal human brain. Atroplne ant BZ were alike in bladlag capacity to these altes. Becanae of the high affinity of BZ for ~uscarlsic receptors, Ya3a~ura ant Snyder (3) were first to show it.S binding to postaynaptlc sites, but failed to find evidence of presynaptlc aides in the CNS. The auggeation by Polak and Meews (4) that the increased release of acetylcholine in viva could be accounted for by blockade of "presynaptic" muscarinic receptors therefore requires another explanation. An early finding by Sacktor (5) ts that acetylcholine (~.6 x 10-5 M) increases phoaphatidyI-~-serine, as well as phosphoinositite and phos~hatidic acid. In addition, atropine (~.6 x 10-6 H) and BZ (7 x 10~3 M) blocked the ACh-stimulated incorporation Of J2po into phosphoinosicidea, but atimulatet lacorporation of labeled phosphate into phoaphatidyl aerlne. This suggests that, although events relates to muscarinic receptor action are blocked by antimnacarinic drugs, other actions may be stimulated. It is known that calcium ions activate phospholipase-C and stimulate the turnover of phoapholiplds, such as triphosphoinooltides, in excitable membranes. Calcium ions have diverse functions in the regulation of cell function. They are required for the release of acetylcholine (6) in neuromuscular transmission ant they influence threshold and other attributes of CNS action potentiala. It is estimated that intracellular "ionized" calcium is low in neurons (about 10-7 M). A small rice in intracellular calcium will produce a sharp rise in Kid conductance, hyperpolarization, ant tepreselon of excitability. The slowed excitation of central neurons by the muscarinic actions of acetylcholine may be countered by anticholinerglc drugs and thus account for many of the central effects of BZ in volunteers reported *Professor and Chairman, Department of Pharmacology' Temple University School of Medicine, Philadelphla, Pennsylvania 19140. K 1

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by Ket chum (7) and by Sidell (8). Moat prominent among these are amnesia, confusion, and disorientation lasting 2 to 6 d. Although the effects of BZ are qualitatively similar to the pharmacologic actions of atropine ant scopolamine, the potency and especially the duration of action of BZ are considerably greater. That situation Is very likely related to properties other than the binding affinity, which is about the came for all these compounds for the muscarlnic receptor (KD - 10-9 M). The ~ -bond properties of quinuclidinyl compounds probably account for their "sticking" to tissue constituents for long periods. Experimentally, a S-~g~kg dose of ratiolabeled BZ prevented auditory stimuli for 7-S 6, but labeled drug was hardly detectable in brain after 3 d. Unfortunately, the only thorough study wee that by Gosselin et al., (9), on [14Clatropine, so direct comparisons are difficult. Although atropine abuse with 2,5-dimethoxy-4-ethyl amphetamine (STP) has been reported (10), the number of "bad trips" made its popularity short-lived. The absence of further reports on abuse of atropine-like drugs suggests that their abuse by the volunteers in question does cot constitute a long-tens problem e Administration of atropine or scopolamine to animals increases acetylcholine output from the exposed cerebral cortex Waldo This has led to the hypothesis of a direct effect on presynaptic muscarinic receptors that regulate ACh release. The finding of release when Ca2+-free Ringer's solution is present (12) led to the suggestion that interneurons are more sensitive to a local decrease in Ca2+ ions than the cholinergic nerve endings whose release they modulate. Alternatively, the ability of BZ, Ditran, and other anticholinergic drugs to cause the release of calcium from intraneuronal binding sites (13) could also explain the in viva observations. The role of ionized calcium in eke release of ACh in neuromuscular ant elec troplax prepare tions i s well charac teri zed . It is persuasively argued that, when ACh emerges from a terminal, it has to pass through some sort of 'gate" that is a Ca2+-dependent channel; the 'gate' is more likely to be open when the terminal ts depolarized. The suggestion that control of ACh release is at the level of calcium displacement by BZ is important, because it is the ca2+-dependent property of 'antichollnergic drugs, ant not their antimuscarinic actions, that explains why BZ and Ditran are much more active than atropine centrally. Hey appear to be equally effective peripherally, when comparisons are based on affinity for muscarinic binding sites. Calcium ion contents can be regulated by any of the membrane systems that are in contact with the cytosol, e.g., plaama membrane, endoplaamic reticulum, and mitochondrial inner membrane. In brain, mitochondria are in the highest concentration at nerve terminals and represent the mayor supplier of cellular energy (ATE). Hitochondria can take up Ca2+ ions by an energy-requiri ng process and release free Ca2' in exchange for Na+ ions. The high capacity of isolated brain mitochondria to transport Cal+ ions has led Lo the suggestion of a significant role for this organelle in ionic homeostasis. The early observations on energy metabolism demonstrated that Ditran and BZ selectively interfered with the increased energy needs in vitro of depolarized cerebral tissue. In contrast, atropine and scopolamine were either without effect or active only at much higher concentration. In the presence of K 2

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isolated brain mitochondria, Ditran (JB339) was shown taco interfere with AIP production (13~. Calcium retention by brain mitochondria is 108 t when energy generation (ATP) is interfered with (14~. The significance of these and other studies is that BZ and Ditran are quantitatively different from the less-potent atropine and scopolamine. A selective action on Ca2+ channels by BE and Divan on particularly vulnerable neurons would explain the unevenness in the correlation between the receptor-binting properties and behavioral alteration by antimuacarlcic compounds in animale and man. CONCLUSION Report s of biochemical effects of anticholinergic compounds contain data on animals and may or may not permit extrapolation to man. There is evidence that the actions of quinuclidine derivatives are longer-lasting ant the limited metabolic data available suggest that they may be retained in tissues for a longer period. Peripherally, the benzilates are acetylcholine antagonista with high affinity (low KDs). They bind reverelbly to muscarinic receptors. Centrally, however, their actions are more complex, and pharmacodynamic and phar~acokinetlc properties play an essential roles The available evidence is not entirely convincing that their basis of central action is through postoynaptic muscarinic receptor binding,, and their pre synaptic role in calcium metabolic must be seriously considered. Without morbidity data, our present biochemical information cannot help to predict long-term effects of exposure to anticholinerglc agents. K 3

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REFEREltCES . _ I. Jovic, R.C. and Zupanc, S. 1973: Inhibition of Stlmulated Cerebral Resplration in-,ritro and Oxygen Conoumption in vlvo in Rats Treated by Cholinolytic Drugs. Biochem. Pharmacol. 22 :1189-1194. 2. 3. Yamamura, H., Wastek, G. J., Johnson9 P.C. and Stern, L.Z. 1978: Blochemical Characterization of Muscarinic Cholinerglc Receptors in Huntington's Dise~ase. Pgs., 35-60 in Cholinergic M~chanisms and Psychop}'armacology. D.J. Jenden, Edo ~ Plenum Press, New York, New York. Yamamura, H. I . and Sayder, S .H. 1974: Post-syuspeic Localization of Muscarinic Cholinerg ic Receptor Bindin8 in Rat Hippocampus. Brain Re~. 78: 320-326. 4. Polak, R.L. and Meews, M.M. 1966: Biochem. Pharmacol. 15:989-992. 5. Report f or Physiol . Div . Sacktor, B. 1961: CRDL Tech. Memo. 23-25 QuarterlY Pro~ress 6. del Castillo, J. and Katz, B . 1955: J. Physiol. 128: 396-411. Ketchum, J.S. 1963: The Human Assessment of BZ C8DL Tech .Hemo 20~29. B. Sidell, F.R. 1960~79: A Sumnlary of the Investigations in Han with BZ Conducted by the US Army. 9. Gosselin, R.E., Gabourel, J.D., Kalser, S.C. and Wills, J.H. 1955: The Hetabolism of 14C-labeled Atropine and Tropic Acid in Mice. Chem. Corps. Med. Lab. Res. Rprt. No. 339; ibid, JPE'r Il5: 217-229. 10. Ilofmann, F.G. 1975: A Handbook on Drug and Alcohol Abuse. Pg. 218-219, ~cford Univerelty Press, New York, London, Toronto. Polak, R.L. 1965: J. Phy~iol. (Lond. ~ 181 :144-1S2. 12. Randic, M. and PadJen, A. 1967: Nature (Lond . ) 215: 990. 13. Melamed, B. and O'~eill, J.J. 1979: Effects of anticholinergic compounds on calcium metabolism in rat brain. The Phar~acologist 21 :~. 14. O'Neill, J. J., Terminl , T. and Walker, J.G. 1972: Biochemical Effects of Psychotomimetic A~ticholinergic Drugs. Adv. in Biochem. Psychopharmacol. 6: 203-218. 15. Tdioe, S-.A., .~nian, A.A. and O'Neill J.J. 1972: Calcium Efflux and Respiratory Inhibition in Brain Hitochondria. BBRC 48: 212-218. K 4