248 The opium analgesics

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Hortense Stevenson
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1 12

2 N CH 3 MeO. R'O* R

3 248 The opium analgesics Chinese decision one

4 Morphine Morphine Structure and properties MeN N CH3 N CH3 Fig Structure

6 Morphine

8 Morphine 253 To conclude, the 6-hydroxyl group is not required for analgesic activity and its removal can be beneficial to analgesic activity. The double bond at 7-8 Several analogues including dihydromorphine (Fig. 12.6) have shown that

10 Development of morphine analogues 255 morphine. Let us consider a diagrammatic representation of morphine as a T-shaped block with

12 Development

13 258 The opium analgesics R= CH 2 -CH=CH 2 ^ Allyl Antagonists NALORPHINE NALOXONE Fig

14 Development of morphine analogues 259 But how can this be? How can a compound be an antagonist of morphine but also act

15 260 The opium analgesics (A) BINDING

16 Development

17 262 The opium analgesics morphine. Notice that the two methyl groups in metazocine are cis with respect to each other and represent the 'stumps' of the C ring. If

18 Development

19 264 The opium analgesics o N C CH=CH-Ph Et 2 C \ / V.^V^ ^ -- N C CH=CH-Ph H \ Fig Effect 3Qx more potent than pethidine Zero Activity

20 Development of morphine analogues 265 Chiral Centre R

21 266 The opium analgesics morphine

22 Development of morphine analogues 267 RMgBr NMe Grignard NMe MeO MeO Fig Drug extension. MeN ' [Complcxedl MeN Fig Grignard reaction leads

24 Receptor theory

25 270 The opium analgesics analgesic has to cross the blood-brain barrier as the free base, but once across has to be ionized in order to interact with the receptor.

26 Receptor theory

27 272 The opium analgesics acts as a partial agonist at the JJL receptor to produce its analgesic effect. This might suggest that buprenorphine should suffer the same side-effects as morphine. The fact that

28 Agonists

30 Enkephalins

32 be Receptor mechanisms 277

33 278 The opium analgesics narcotic analgesics. There is still a search to see if there are possibly two slightly different mu receptors, one which is solely due to analgesia and one responsible for the side-effects

34 membrane to a second membrane-bound protein. This protein then acts The future 279

35 280 The opium analgesics O II N C-CH 2 N-CH2-^ Ethylketocyclazocine (Kappa=mu > delta) U (kappa

36 13

38 In

39 284 Cimetidine a rational approach to drug design 13.3 Histamine Histamine

40 Searching

42 Searching

44 Searching for a lead AT-guanylhistamine 289 as long as A/^-guanylhistamine is bound to the receptor, it prevents histamine from binding

45 290 Cimetidine a rational approach to drug design reach

46 Developing the lead a chelation bonding theory 291 HN ch 2 -ch 2 -x c' N I H H Strong Interaction Weak Interaction >- RECEPTOR X=NH, S RECEPTOR X=Me,

48 From partial agonist

50 Development of metiamide 295 meaning that the ring is a weak base and mostly un-ionized. The pk a value for imidazole itself

Development of metiamide 297 the same pk a as for imidazole itself, which shows that the electronic effects of the methyl group and the side-chain are cancelling each other out as far

52 Development of metiamide 297 the same pk a as for imidazole itself, which shows that the electronic effects of the methyl group and the side-chain are cancelling each other out as far as pk a is concerned.) A pk a of 6.80 means that 20 per cent of metiamide is ionized in the imidazole ring. However, this is still significantly lower than the corresponding 40 per cent

54 Development

56 Cimetidine

58 Further studies cimetidine analogues

59 304 Cimetidine a rational approach to drug design they are likely to be highly solvated (i.e. surrounded by a 'water coat'). Before hydrogen bonding can take place to the receptor, this 'water coat' has to be removed. The more solvated the group, the more difficult that will be.

60 Further studies cimetidine analogues

61 306 Cimetidine a rational approach to drug design Me N P* / \ Fig Cimetidine analogue with a nitroketeneaminal group. HN^\ I V-CH 2-S CH 2-CH 2-NH-C V l^_ # H

62 Further studies cimetidine analogues NC, OjjN "S, =-6 =16.7 I * ^H k 4> =27 H =14.2 NMe H =33 =15.1 Fig Dipole moments

63 308 Cimetidine a rational approach to drug design dipole moment

64 Famotidine and nizatidine 309 Replacing the sulfur atom with a methylene unit leads to a drop in activity. Placing the sulfur next to the ring lowers activity. Replacing the furan ring with more hydrophobic rings such as phenyl or thiophene reduces activity.

67 312 Cimetidine a rational approach to drug design effects.

68 Appendix

69 Appendix

70 (vesicles) containing The action of nerves 315

72 a The action of nerves 317

74 The action of nerves 319 x Briv "-

75 Appendix

76 Secondary messengers

77 322 Secondary messengers number

78 Secondary messengers 323 the process shown o=co=

80 Secondary messengers

81 Appendix 4 Bacteria and bacterial nomenclature Bacterial nomenclature COCCI (Spherical) BACILLI (Cylindrical) STREPTOCOCCI (Chains) Fig. A4.1 Bacterial nomenclature. STAPHYLOCOCCI (Clusters) Some clinically important bacteria Organism Staphylococcus aureus Gram Positive Infections Skin Streptococcus Escherichia coli Positive Negative Proteus species Salmonella species Shigella species Enterobacter species Pseudomonas aeruginosa Negative Negative Negative Negative Negative

82 Haemophilus influenzae Bacteroides fragilis Negative Negative Bacteria and bacterial nomenclature 327 patients, i.e. cancer patients, commonly causes chest infections

83 Glossary ADDICTION Addiction can be defined as a habitual form of behaviour. It need not be harmful.

84 Glossary

85 Further reading Albert,

86 Index acetylcholine 47-8, 207, , , 243, 282, 315,

88 drug addiction 1, 3, 5, 127, 248, 262-3, 271-2, Index 333

89 334 Index intestinal infections

90 penillic acids 172 pentagastrin Index 335

91 336 Index structure-activity analysis (SAR) 82, 84-9, 248 acetylcholine aryl tetrazolylalkanoic acids benzenesulfonamides

Creating a User Defined Pneumonia-Specific Syndrome in ESSENCE. Preventive Medicine Directorate September 2016

Creating a User Defined Pneumonia-Specific Syndrome in ESSENCE Preventive Medicine Directorate September 2016 0 Pneumonia-Specific Syndrome NMCPHC retrospective analyses suggest that surveillance using