The action of structural analogues of nicotine on synaptic transmission

The Relevance of Nicotine to the Study of Synaptic Transmission I. 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 Conclusion II 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 38 III 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 45 IV 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 67 Results: 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 76 DISCUSSION: 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 95.