The Steric Factor in Medicinal Chemistry Dissymmetric Probes of Pharmacological Receptors

Size: px

Start display at page:

Download "The Steric Factor in Medicinal Chemistry Dissymmetric Probes of Pharmacological Receptors"

Eric Riley
5 years ago
Views:

1 The Steric Factor in Medicinal Chemistry Dissymmetric Probes of Pharmacological Receptors Alan F. Casy University of Bath Bath, United Kingdom With a contribution by George H. Dewar University of Bath Bath, United Kingdom Plenum Press New York and London

2 Contents 1. Introduction Purpose and Value of Stereochemical Investigations in Medicinal Chemistry Concepts Conformational Effects Pfeiffer's Rule Ogston's Ideas and Prochirality Pattern of Presentation Notes on References 9 References 9 2. Nomenclature and Methodology Introduction Stereochemical Nomenclature and Methodology Cyclic Systems Geometrical Isomers Methods of Establishing Relative and Absolute Stereochemistry Computational Methods Sources of Stereoisomers Resolution Use of Chiral Building Blocks Use of Enzymes in Chiral Synthesis Use of Chiral Auxiliaries Chiral Analysis Chromatographic Methods Chiral Recognition via Host-Guest Complexation NMR Procedures Pseudoracemates Radioimmunoassay Pharmacological Methods Whole Animal (in Vivo) Experiments 43

3 Isolated Tissue (in Vitro) Procedures Binding Experiments Biochemical Assays General Remark 45 References Pharmacokinetics: Including Use of Racemic Mixtures in Therapy Introduction Distribution and Protein Binding Warfarin Metabolism Examples Hexobarbital Pentobarbital Mephenytoin Anticoagulants Acenocoumarol Verapamil Terbutaline Therapeutic Use of Chiral Drugs in Racemic Mixture Form Metabolic Interactions between Enantiomers Biliary and Renal Excretion Significance 67 References Adrenergic Ligands: Chiefly Agonists Introduction Natural Catecholamines and Synthetic Agents with Direct Action Aspects of in Vivo Synthesis Isoprenaline and Other Agents of Primarily P-Agonist Character Labetalol and Other Combined a, p blockers The Easson and Stedman Hypothesis Phenethylamines with a-carbon Chirality Octopamines and Synephrines Imidazolines Trimetoquinol (TMQ) Adrenergic Agents with Indirect and Mixed Actions (False Transmitters) Conformational Studies Spectral Analysis Ill Conformational Restraints Binding Experiments and Influence of Adrenoceptor Ligands on Adenylate Cyclase 119 Appendix: Reserpine 121 References 122

4 xvii 5. Adrenoceptor Antagonists Introduction a-antagonists Benzodioxans Yohimbine and Its Stereoisomers and Analogues Stereochemistry of Yohimbine and its Stereoisomers Miscellaneous Agents P-Antagonists Second-Generation P-Blockers Pharmacokinetics of Propranolol and Its Analogues Stereoselective Synthesis Timolol Oxime Class Further Analogues Including a-methyl Derivatives Conformational Aspects 159 References Dopamine and Dopaminergic Ligands Introduction Conformational Studies Methylated and Small-Ring Analogues of Dopamine P-Hydroxy Analogues Small-Ring Analogues Aporphines Aminotetralins Phenylpiperidines Ergot Derivatives Octahydrobenzo[/]quinolines Octahydrobenzo[g]quinolines Miscellaneous Agonists Including Benzazepines Models Cocaine and Dopamine 202 References Dopamine Antagonists Introduction Thioxanthenes Butaclamol and Related Benzocycloheptapyridoisoquinolines Dibenzo[6,/]thiepins and Related Compounds Benzamides Halogenated Benzazepines Miscellaneous Antagonists 225 References Cholinergic Agonists Introduction Methylated Analogues of Acetylcholine 231

5 xviii 8.3. Muscarine and Its Analogues Muscarone Analogues and Cyclopentane Derivatives Muscarine Analogues Cyclopentane Derivatives Conformational Studies NMR (Chiefly 'H) Studies of Conformation Methylacetylcholines Molecular Orbital (MO) Calculations of Conformation Conformationally Restrained Analogues of Muscarinic Agonists Analogues of ACh Derivatives of Quinuclidine and Related Bicyclic Agonists Piperidine and Thiane Analogues Metabolic Inactivation of ACh and AChE Inhibitors Storages and Release of ACh 280 References Muscarinic Antagonists Introduction: Tropane Alkaloids Orientation of the Acyloxy Function in Relation to the Basic Nitrogen of Tropane and Piperidyl Anticholinergics Choline Derivatives Dioxolane and 1,3-Oxathiolane Derivatives Quinuclidines Procyclidine, Benzhexol, and Miscellaneous Anticholinergics Chiral Oxotremorine Derivatives Chiral Analogues of Pirenzepine 319 References Ligands of Nicotinic Cholinergic Receptors (nachr) Including Neuromuscular Blocking Agents Introduction Nicotine Cytisine and Other Agonists Stereo-SAR Analyses Nicotinic Receptor Antagonists: Neuromuscular Blocking (NMB) Agents Nondepolarizing Agents Depolarizing Agents Stereochemistry in Nondepolarizing NMB Agents Tubocurarine and Closely Related Substances Synthetic, Symmetrical 1-Benzylisoquinolinium Agents Alkaloids of Calabash Curare (Strychnos) Steroidal Neuromuscular Blocking Agents Miscellaneous NMB Agents Stereochemistry in Depolarizing Agents Snake Neurotoxins Other Toxins 360 References 361

6 xix 11. Histamine Receptors: Agonists and Antagonists Histamine: Biogenesis and Metabolism Receptor Subtypes and Agonist Conformation Chiral and Restrained Analogues of Histamine and Impromidine Antagonists of H,-Receptors: Testing Methods Tertiary Aminoalkyl Ethers Amino-l-aryl-l-(2-pyridyl)propanes (Pheniramines) Tricyclic Antihistamines Miscellaneous Antihistamines Geometrical Isomers Configurational Studies Pyrrobutamine and Related l,2-diaryl-4-aminobutenes Conformational Analysis of Antihistamines General Remarks Isomeric Potency and Affinity Ratios Conformationally Restrained Antihistamines of Cyclic Nature Central Effects 405 References Hydroxytryptamine Ligands Introduction Uptake Inhibition Chiral Ligands Hydroxy-DPAT Methyl Analogues Methyl Analogues Phenalkylamines Chiral 5-HT Antagonists HT 3 Ligands Mapping of Agonist Sites 425 References Opioid Ligands: Part Introduction Morphine and Congeners Derived from Opium Alkaloids B/C /raws-morphine Ring C Diastereoisomers Amino Derivatives: Affinity Ligands Bivalent Ligands Substituents at C Quaternary Salts Thebaine-Derived Opiates: Etorphine and Its Relatives Morphinans B/C trans Series: Isomorphinans and Other Analogues ,7-Benzomorphans Hydroxy Derivatives Arylpiperidines 465

7 xx Arylmorphans Arylpiperidines Phenylpiperidines with C-4 Oxygen Substituents a- and P-Prodine and Related Compounds Analysis of Stereostructure-Activity Relationships in 4-Phenylpiperidine Reversed Esters Stereochemical Methods Receptor Speculations 491 References Opioid Ligands: Part Introduction Fentanyl Group Methadone and Related 3,3-Diphenylpropylamines Opioid Peptides Nonalkenic Cyclic Analogues Miscellaneous Opioids Tetrahydroisoquinolines Cyclohexane Derivatives Kappa (K) Agonists: U and its Relatives Aminotetralins Viminol 543 References 544 Appendix and Postscript 549 References 551 Index 553

Module Objectives: Why to study Organic Pharmaceutical Chemistry? 24-Oct-17

Module Objectives: Why to study Organic Pharmaceutical Chemistry? 24-Oct-17 1 2 Useful Info: Students are encouraged to visit the faculty website: http://pharmacy.uokerbala.edu.iq/ And most importantly the e-learning website: http://elearning.uokerbala.edu.iq Nevertheless, feel