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EVALUATION OF THE PROBABLE CHOLINERGIC EFFECTS OF BDF 8503.
TABLE OF CONTENT
DECLARATION
DEDICATION
ACKNOWLEDGEMENT
TABLE OF CONTENTS
ABSTRACTS
CHAPTER ONE
LITERATURE REVIEW
1.1
GENERAL INTRODUCTION
1.2
ACETYLCHOLINE
1.3
PRAZOBIN
1.4
PIRENZEPINE
1.5
BDF 8503
1.6
AIMS OF PROJECT
CHAPTER TWO
2.1 MATERIALS
2.2 METHOD
2.3 THE GUINEA – PIG ILEUM
2.4 PRECAUTIONS TAKEN
2.5 STATISTICS
CHAPTER
THREE
3.1 RESULTS
CHAPTER
FOUR
4.1 DISCUSSION
4.2 MODEL
4.3 SUMMARY AND CONCLUSION
REFERENCES
Abstracts
(1) The
effects of BDF 8503 (10-6m) on the response of the guinea – pig
ileum to Ach. Were investigated.
(2) The
effects of 10-8m – 10-7m of prezosin on the Ach
contractile response on the guinea –pig ileum were also investigated.
(3) BDF
8503 potentiated the contractile response to Ach. This was evidenced by the
shift of the dose-response curve to the left, the increase in Emax and the fall
in Ec50. An inverse relationship between the doses of BDF 8503 used
and the degree of potentiation was observed. No change in baseline was
observed.
(4) Prazosin
(10-8-10-7m) produced similar results as was obtained
with BDF 8503, in addition to an increase in baseline.
(5) BDF
8503 still potentiated responses to Ach when coadministered with prazosin.
Prazosin was allowed a contact time of 15 minutes before BDF 8503 was added.
(6) BDF
8503 potential responses to Ach when coadministered with prazosin and
pirenzepine.
(7) 
These results suggest that:
(a) the potentiating effects of BDF 8503 may be mediated via a selective 1 – adrendceptor blockade. (b) a
non 1 – adrenoceptor
mechanism, such as the sensitization of muscarinic receptors or activation of
other unknown receptors, may be involved.
Further investigations,
using an 1 agonist
such as phenylephrine, M1- cholinoceptor agonist such as MCN – A –
343 and an M2 – cholinoceptor antagonist such as atropine,. Have
been suggested.
Chapter one
Literature review
1.1
general introduction
The introduction
of a new drug candidate is usually followed by a period of screening for
characterization of its pharmacologival profile. The screening for
characterization of its pharmacological profile. The screening is done first in
animals, and then in man.
The
choice of a screening procedure is more often influenced by: the reliability
and sensitivity of the test; the simplicity of the test; and the type of drug
being studied. Indeed, no screening procedure can be perfect. Hence, it is
imperative that anyone performing a screening test should be vigilant for
borderline results and for results indicating and borderline results for
results indicating an inactive substance even when one strongly suspects that
activity may be present.
Generally,
it is better to use a screening test which gives a few type II errors
(accepting and inactive substance as being active), this is because, if a
substance has no true activity but is shown by a test to be active (type II
error), sooner or later as testing with the substance is continued, its
inactivity will be revealed. Although some time may be wasted in studying the
compound, in the end the investigator is not misled. Conversely, when an active
substance is rejected being inactive (type I error), it may result in its removal
from further study, so that its activity will remain forever undetected. One
important approach in reducing both types of error is to increase the sample
size, which may or may not be possible.
An
important factor common to all screening methods is that they require the
exercise of judgement and discretion on the part of the investigator. The
quality of such a judgement would invariably depend on the investigators
knowledge of the tools used in his investigation. Hence, a brief summary of the
pharmacology of acetylcholine (Ach), prazosin and pirezepine – which are the
tools used in this study on BDF 8503 – is imperative.
1.2
acetylcholine (Ach)
Ach, which was first
synthesized by Baeyer in 1867, is an endogenous neutransmitter found in many
parts of the body such as:
(1) autonomic
effector sites innervated by post-ganglionic parasympathetic fibres;
(2) sympathetic
and parasympathetic ganglion cells and the adrenal medullar, innervated by
pre-ganglionic autonomic fibres;
(3) moto
end-plates on skeletal muscles, innervated by somatic motor nerves; and
(4) certain
synapses within the central nervous system (CNS). The amount of Ach in the body
has not been assayed. However, it has been estimated that the guinea=pig
intestine, when assayed for Ach on frog rectus muscle, contains 54.8n mole/g of
ach (Feldberg and Lin, 1950).
STRUCTURE/STRUCTURE
– ACTIVITY RELATIONSHIPS:
1 2 3
4 5
6
(CH3)3
N+- CH2-
CH2-o – C – CH3
The structure of Ach is shown
above. Substitution of the (CH3) moiety at position 1 with (NH2)
group, as exemplified by carbachol, leads to a loss in susceptibility to
cholinesterase reduction. Addition of a methyl group at position 4 results in a
reduction in both nicotinic activity and susceptibility to cholinesterase
reduction. This is also exemplified by methacholine – a derivative of
acetylcholine (Watanabe, 1984).
Mechanisms of action:
The
pharmacological effects of Ach are mediated via its binding to muscarinic and
nicotinic receptors. There are at least 3 subtypes of muscarinic receptors
termed M1 M2, and M3 (De Jorge et al; 1986).
M1
receptors are found in the cerebral cortex and to a lesser extent in autonomic
ganglionic cells. This receptor has a high affinity for pirenzepine.
Conversely, N2 receptors have a low pirenzepine affinity but high
methoctramine and AF- Dx116 affinity. M2 receptors are found in the
heart, central neutral neurones, as well as in the guinea-pig ileum (De Jorge
et al., 1986). M3 receptors abound in gland tissues, and have low
affinity for AF-Dx 116 and methctramine. An atypical muscarinic receptor has
recently been described by Michel et al. (1988).
The
cellular events following the interaction of Ach with its muscarine receptors
are not well understood. Available evidence however, suggest that it might
involve one or more of the following primary events:
(1) an
increase in concentration of cyclic guanosine mono-phosphate (CGMP), presumably
by activating guanylate cyclase which catalyses the conversion of guanasine
triphosphate (GTP) to CGMP;
(2) an
increase in inositol phospholipid turnover in cellular membranes;
(3) inhibition
of adenyl cyclase activity in specific organs, that is the heart.
The
interaction of Ach with nicotinic receptors (found in the autonomic ganglia,
striated muscles and central neurones), results in a conformational change in
the receptors protein that allows Na+ and k+ to diffuse
Ach has a broad pharmacological
action in the organs and systems of the body. These actions shall be considered
systemically.
CARDIOVASCULAR SYSTEM (CVS):
The main effects of Ach on the cvs
are the reduction in peripheral vascular resistance and changes in heart rate.
Intravenous infusions of minimal effective doses of Ach in man (20-50ng/min)
causes vasodilatation which results in a reduction in blood pressure, and if
often accompanied by a reflex increase in heart rate. Larger doses produce
bradycardia and decreased conduction velocity through the atrioventricular
node, in addition to the hypotensive effect.
GASTRO INTESTINAL TRACK:
Ach stimulates the parasympathetic
system to the gut and causes an increase in secretory as well as motor
activity. The salivary and gastric glands are strongly stimulated – the
intestinal glands are strongly stimulated – the intestinal glands less so.
Peristaltic activity is increased throughout the gut and most sphincters are
relaxed. Similar effects may occur in the guinea pig intestine.
The
instillation of Ach into the conjunctiva sac causes contraction of the smooth
muscles of the iris Intra-ocular pressure is also decreased by facilitating the
out flow of aqueous homor into the canal of Schlem which drains the anterior
chamber of the age.
RESPIRATORY SYSTEM:
Ach stimulates the glandular
secretions of the tracheobronchial glands. It also stimulates the contraction
of the smooth muscles of the brochial tree.
GENITOURINARY TRACT :
The
detrusor muscle is stimulated to contract while the trigone and sphincter
muscle of the bladder are relaxed – this promoting voiding of urine.
Neuromuscular junction:
When
Ach is applied directly (by iontophoresis or by intra-arterial injection), an
immediate depolarization of the end-plate results. This causes an increase in
permeability to Na+ and results in a contractile response.
Central nervous system (CVS)
The
brain has a preponderance of muscarinic to nicotinic receptors, while the
converse is the case in the spinal cord. Despite this, however, nicotine has
very important effects on the brain stem and cortex. In moderate doses, Ach
acts on nicotinic receptors and causes a mild alerting effect on the CNS.
Higher doses cause tremor, emesis and stimulation of the respiratory centre,
while still higher doses cause convulsion which might terminate in fatal coma.
Pharmacokinetics:
Ach is rarely used therapeutically.
However, a 1% solution of Ach is available for sue in cataract extractions and
certain other surgical procedures on the anterio segment of the eye when it isa
desired to produce miosis rapidly.
1.3
PRAZOSIN
Prazosin is a selective d1 –
adrenoceptor anatagonost effective in hypertension. It has the chemical
structure shown below.
Mode of action:
Prazosin selectively antagonise d1 – (post-synaptic)
adrenoceptors and causes peripheral arteriolar vasodilation which leads to a
fall in blood pressure in hypertension, and a decrease in after-load in cardiac
failure.
The
hypotension produced by tarchycardia because d2 (presynaptic) adrenoceptors are
not affected by prazosin, which, when otherwise blocked, would cause further
release of noradrenamone and subsequent tarchycardia. This is observed with the
non-selective d (- adrenoceptor antagonosts such as phetolamone and
phenoxybenzamine.
Phosphodiesterae
and dopamine – B – dydroxylase inhibition occurs with prazosin, but only at
concentrations much higher than are found during therapy, and hence might not
contribute to its clinical effects (Grahame-smith and Aronson, 1985).
ADVERSE EFFECTS:
Dizziness and less of consciousness may occur
following the first dose of prazosin, due to profound hypotension
(Grahame-smith and aronson, 1985). This effect is especially marked in patients
taking diuretics or B-adrenoceptor
antagonists. Other common adverse effects are: other common adverse effects
are: dry mouth; headache; postural dizziness; and tarchycardia.
USES
Prazosin is used in chronic heart failure and
hypertension.
1.4
PIRENZEPINE
This drug is a tricyclic
benzodiazepine derivative having a molecular weight of 424.3 and the chemical formula
shown below:
C19H212N5O21
2 HCL.
It was Goyal and Raltan
(1978), on the basis of a study with the selective muscarinic agonist _
MCN-A-343, who first proposed the existence of M1-receptors on inhibitory
neurones in the oesophagus of the opossum. This, they subsequently confirmed in
1984, using pirenzepine. Other workers have also shown that pirezenpine hs a
low affinity for human gut-smooth muscle M1 receptors, and inhibits colonic
contractile pressure in man only at high plasma levels. Intravenous doses of
atropine and pirenzepine are equipotent with respect t oinhibition of gastric
secretion (Abrahamson, et al;. 1985).
Low doses of pirenzepine (0.1-1.0 nM) significantly
enhances peristalsis in the guinea-pig ileum, whereas larger concentrations
causes inhibition (Schworrer and killbinger, 1988). Since stimulation of ileal
M1 receptors have been demonstrated to be inhibitory (Schuurkes el al 1988).
Since stimulation of ileum M1 receptors have been demonstrated to be inhibitory
(Schuurkes at. Al 1988), and blocker of M2 receptors t obe inhibitory on
persistatic activity (Schworer and Kilbinger, 1988), it has been suggested that
low doses of pirenzepine selectively blocks M1 receptors while higher doses
block M2 receptors as well (Schworer and Kilbinger, 1988).
Evidence for ZM1-receptors
on enteric nerve cells have been provided by in situmotility studies; binding
studies; autoradiography; in vitro Ach release; and in vivo motility studies
(Bettrarello, 1985). Pirenzepine is used therapeutically in peptic ulcers and
non-ulcer dyspepsia.
1.5
BDF 8503
This is pale yellow powder
of molecular weight 411.51 and the chemical formula:
C22H29
N5o3
It is thought to be a
selective di adrenoceptor antagonist, more potent and having a longer duration
of action than prazosin. It has a PA2 of 9.2. is still undergoing
trial-0hence it s literature is scanty.
1.6 AIMS OF PROJECT
BDF 8503 had been shown in a previous study to
potentiate the contractile response of the guinea – pig ileum to Ach
(Amarachukwu, personal communication, (1988). The aims of this study therefore,
were:
(1) To
confirm previous observations of the effects of BDF 8503 on Ach contractile
response;
(2) To
elucidate the mechanism for the above potentiation of Ach – induced contratile
responses;
(3) 
To compare these effects
with those prazosin, a known 1 – adrenoceptors antagonist in order to
determine whether this properties is common to 1 blockers or an additional properties of BDF
8503.
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