Analgesics structures

Codd, E. E., Shank, R. P., Schupsky, J. J., Raffa, R. B. Serotonin and norepinephrine uptake inhibiting activity of centrally acting analgesics structural determinants and role in antinociception, J. Pharmacol. Exp. Ther. 1995, 274, 1263-1270. 

Some examples from our recent study of opiate analgesic structures (8,24) serve to illustrate further the types of information which a combined approach can provide. The approach used in this study was 1) accumulate accurate crystal structure results on representative compounds by literature search and performing crystal structure determinations, then 2) develop and verify molecular mechanics potential parameters for use with analgesics, and 3) perform strain energy calculations to find active conformations by comparing different chemical structural types which act at a common receptor. The object of the study was to 1) better define the three-dimensional requirements of opiate analgesics, and 2) better understand the opiate receptor itself by indirectly investigating it. 

On the basis of these and other studies Bentley and his colleagues5,6 have proposed a hypothetical receptor site (V) which will accommodate these new molecules as well as the older analgesic structures... 

A., Ghelardini, C., Galeotti, N Anderson, D.J., Kuntzweiler, T.A., Colombo, D., Toma, L., 1998. Mono- and disubstituted-3,8-diazabi-cyclo[3.2.1]octane derivatives as analgesics structurally related to epibatidine synthesis, activity and modeling. J. Med. Chem. 41, 674-681. 

Another analgesic, structurally similar to aspirin, that has foimd some application is salicylamide. Salicylamide is a n ingredient in some pain-relief preparations, although its use is declining. 

Methadone is a potent synthetic opioid analgesic, structurally unrelated to any of the opium-derived alkaloids. It is a highly lipophilic, basic drug (pKa 9.2) available as a hydrochloride powder formulation that can be reconstituted for oral, rectal, or parenteral administration. Methadone was developed in Germany in 1942 as a synthetic substitute for morphine, and has been approved and widely employed for opioid detoxification maintenance as well as acute and chronic pain management. 

Literature reports over the last year indicate some decrease in the amount of chemical effort devoted to new analgesic structures, but a continued increase in investigation of biochemical mechanisms of analgesia and dependence. Interest in narcotic antagonists for the treatment and prevention of narcotic abuse has stimulated much current research on new compounds. In neither area was there evidence of a significant advance during the year. 

A synthesis of the analgesic substance phenacetm is outlined in the following equation What IS the structure of phenacetm ... 

Dibenz[h,e]azepine-6,11-diones ent-Morphinan nomenclature, 1, 29 Morphinan, 1,2,3,4-tetrahydro-nomenclature, 1, 29 14-a-Morphinan, N-methyl-synthesis, 1, 480 Morphinans nomenclature, 1, 29 as pharmaceuticals, 1, 148 synthesis, 2, 377 Morphine, 2, 512 as analgesic, 1, 167 as metabolite of normorphine, 1, 235 as pharmaceutical, 1, 146, 147, 148 synthesis, 1, 480 Morphine alkaloids structure, 4, 534 Morphin-7-en nomenclature, 1, 29 Morphinone, dihydro-as pharmaceutical, 1, 147 Morpholine — see also 1,4-Oxazine, tetrahydrocarcinogenicity, 1, 229 corrosion inhibitor, 1, 409 metabolism, 1, 226 nomenclature, 3, 996 structure, 2, 5 synthesis, 2, 89 Morpholine, 4-aciyloyl-polymers, 1, 291 Morpholine, alkenyl-polymers, 1, 291... 

X-ray structure, 3, 158-159 Phenazin-l(2H)-one, 3,4-dihydro-synthesis, 2, 69 Phenazopyridine, 1, 145 as urinary tract analgesic, 2, 517 Phenbenzamine as antihistamine, 1, 177 Phencyclidine... 

FIGURE 25.29 (a) The structures of several commou analgesic agents. Acetaminophen is marketed under the tradename Tylenol. Ibuprofen is sold as Motrin, Nuprin, and Advil, (b) Acetylsalicylate (aspirin) inhibits the cyclooxygenase activity of endoperoxide synthase via acetylation (covalent modification) of Ser ... 

Incorporation of the benzylic carbon of phenylacetic acid into a cyclohexane ring affords an agent whose activity is closely related to that of the narcotic analgesics. This activity is particularly noteworthy for the fact that this structure repre-... 

Exploratory research on structure activity relationships in the meperidine series revealed the interesting fact that the oxygen atom and carbonyl group of this molecule could often be interchanged. That is, the so-called "reversed meperidine" (C) still exhibits analgesic activity in experimental animals. (Note that, except for the interchange, the rest of the molecule is unchanged.)... 

Still further simplification of the structural requirements for central analgesic activity came from the serendipitous observation that the simple phenyl pi peri dine, meperidine... 

Dezocine (30) represents a class of bridged aminotetralins possessing morphine-like analgesic properties. It appears to be roughly equivalent in potency and addiction potential to morphine. The molecule combines molecular features of precedent aminotetralins and benzomor-phans and its structure fits the classical Morphine Rule. The 1-enantiomer is the more active and the p-epimer (equatorial NHj) is the active diastereomer. 

The majority of analgesics can be classified as either central or peripheral on the basis of their mode of action. Structural characteristics usually follow the same divisions the former show some relation to the opioids while the latter can be recognized as NSAlD s. The triamino pyridine 17 is an analgesic which does not seem to belong stmcturally to either class. Reaction of substituted pyridine 13 (obtainable from 12 by nitration ) with benzylamine 14 leads to the product from replacement of the methoxyl group (15). The reaction probably proceeds by the addition elimination sequence characteristic of heterocyclic nucleophilic displacements. Reduction of the nitro group with Raney nickel gives triamine 16. Acylation of the product with ethyl chlorofor-mate produces flupirtine (17) [4]. 

The search for opioid analgesics which show reduced addiction liability ha.s centered largely on benzomorphan and morphinan derivatives. Some research has, however, been devoted to derivatives of the structurally simpler meperidine series. The preparation of one such compound, picenadol (59), starts with the reaction of N-methyl-4-piperidone with the lithium derivative from m-methoxybromobenzene. Dehydration of the first formed carbinol 51 gives the intermediate 52. Deprotonation by means of butyl lithium gives an anion which can be depicted in the ambident form 53. In the event, treatment of the anion with propyl bromide gives the product 54 from reaction of the benzylic anion. Treatment of that product, which now contains an eneamine function. 

Therapeutic Function Analgesic, antipyretic Chemical Name N-(4-hydroxyphenyl)acetamlde Common Name Paracetamol, Acetylfl-Aminophenol, APAP Structural Formula ... 

Therapeutic Function Analgesic, Anticonvulsant Chemical Name 5H-dibenz[b,f] azepine-5-carboxamide Common Name 5-carbamyl iminostilbene Structural Formula ... 

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