Below are the first 10 and last 10 pages of uncorrected machine-read text (when available) of this chapter, followed by the top 30 algorithmically extracted key phrases from the chapter as a whole.
Intended to provide our own search engines and external engines with highly rich, chapter-representative searchable text on the opening pages of each chapter.
Because it is UNCORRECTED material, please consider the following text as a useful but insufficient proxy for the authoritative book pages.
Do not use for reproduction, copying, pasting, or reading; exclusively for search engines.
OCR for page 271
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
OCR for page 272
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
OCR for page 273
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
OCR for page 274
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
Representative terms from entire chapter:
brain mitochondria
