The Relevance of Nicotine to the Study of
Synaptic TransmissionI. ACTION OF NICOTINE ON TRANSMISSION IN
AUTONOMIC GANGLIA:
Site of Action at Ganglia 1
Chemical Transmitter 3
Identification of Acetylcholine 4
Nicotine -like Activity of Acetylcholine 5
Study of mode of Block 6
Electrophysiological study on Cat
Superior cervical ganglion 7
Depolarisation
Second Phase of Block: Desensitisation? 9
Comparison of Nicotine and
Acetylcholine 11
Study on Isolated Ganglion of Rabbit 12
ConclusionII ACTION OF NICOTINE ON TRANSMISSION AT
THE NEUROMUSCULAR JUNCTION:
Chemical Transmission at Neuromuscular
Junction 14
STIMULANT ACTION OF NICCOTINE:
(a) Contracture 15
(b ) Contraction 16
Presence of Two Types of Fibres 17
(1) Frog 17
(2) Chick 17
Connection between Depolarisation and
Contracture 19
Pharmacological difference between
Fibres 20
Quantitative Comparison of the
Neuromuscular Junction and the
Ganglion 20
BLOCKING ACTIVITY:
Introduction 21
The effects of Decamethonium on the
end-plate 21
The effect of ( +) Tubocurarine on the
end -plate 22
Classification into two types of
block 23
The two Phases of block produced by
Decamethonium 25
Microphysiological Study of Phase II 27
Differences between the effect of
eserine on the block of micro and
macro preparations 28
Kinetic Theory 30
(a) Intermediate Complex 30
(b) Connection between
depolarisation and
desensitisation 31
(c) Facilitation 34
Anticholinestèrase Activity as a Complicating Factor 35
Mode of Block by Nicotine 36
Conclusion 38III RELATIONSHIP BETWEEN CHEMICAL STRUCTURE
AND NICOTINE-LIKE ACTIVITY:
Choline phenyl ethers - Hey's
Hypothesis 40
Hypothesis applied to Nicotine 41
Compounds Prepared 42
Preparations used 45IV PHARMACOLOGY OF RELATED COMPOUNDS 46
EXPERIMENTAL SECTION 48
Methods:
.ACTIVITY AT THE NEUROMUSCULAR JUNCTION
I The Rat Phrenic Nerve -Diaphragm
Preparation 49
Method 5 0
II The Chicken Biventer Cervicis
Preparation 51
Method 52
ACTIVITY AT GANGLIA
The Cat Superior Cervical Ganglion
Preparation 54
Method - (i) Antagonist Activity 56
(ii) Agonist Activity 58
ACTIVITY ON CHOLINESTERASE
Enzyme Source 59
Method - (a? Control Experiments 60
(b Test of Inhibitors 63
Comment
Alternative Method 65
MEASUREMENT OF DISSOCIATION CONSTANTS 67Results:
ACTIVITY AT THE NEUROMUSCULAR JUNCTION
I The Rat Phrenic Nerve - Diaphragm Preparation 71
II The Chick Biventer Cervicis Preparation 72
ACTIVITY AT GANGLIA
The Cat Superior Cervical Ganglion:
a Blocking Activity 73
b Stimulant Activity 74
ACTIVITY ON CHOLINESTERASE 75
DISSOCIATION CONSTANTS 76DISCUSSION:
I SIGNIFICANCE OF THE RESULTS:
Type of Action on the Rat Diaphragm 78
Type of Action on the Cat Ganglion 79
Possibility of an indirect action: 79
Anticholinesterase Activity
Active Species: Ion or Salt 82
II RELATIONSHIPS BETWEEN STRUCTURE AND
ACTIVITY:
(a)Effect of Position of the Side Chain 84
(b) Effect of Chain Length 85
(i) Tertiary Compounds 85
(ii) Quaternary Compounds 86
(c) Effect of Quaternisation 86
(d) Activity Differences in different Tests 87
Points to be explained 89
III SPACIAL CONSIDERATIONS:
Importance of Side Chain Nitrogen 90
Effect of Quaternisation of Side Chain
Nitrogen 91
Importance of Pyridine Ring 91
Conclusion 94
IV THE RELEVANCE OF THIS STUDY TO THE
ACTIVITY OF RELATED COMPOUNDS 95ACKNOWLEDGEMENT 97BIBLIOGRAPHY 9
