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Indirectly by bringing about release of endogenous opioids (p. 363) seems improbable in view of the numerous qualitative differences that they display. Overall speculations on receptor situations (scenarios) devolve on whether multiple or single receptor species are to be considered. The multiple condition in its extreme form requires a collection of distinct (and possibly linked) receptors, each being specific for a particular response (involving pain perception, respiration, etc.) and for a...

Introduction To Opioid Receptors

This book deals with substances commonly described as analgesics or analgetics that alleviate or abolish pain without at the same time inducing loss of consciousness. Their site of action is essentially within the central nervous system whereby they are distinguished from pain-relieving drugs such as aspirin and other anti-inflammatory agents that act at peripheral locations. Their central actions are depressant but they may be differentiated from general agents of this description such as...

Beckett Casy Hypothesis

Alvodine, 232 14-Amidomorphine, 430 Amidone, 303 6-Amino 3,3-diphenylhexan-3-one, 307 9-Aminoarylmorphans, 219 8-Aminobenzomorphans, 182 1-Aminocodeine, 32 i-Aminocyclohexanes, 395 w-Aminohexyl septarose, 448 14 3 Aminomorphine, 448 Ammopeptidases, 337 N-p Aminophenethylnorpethidine, 232 Aminotetralins, 396, 464 Aminotetralins, bndged, 433 Amitnptyline, 236 Androcymbine, 145 Anilendine, 232, 449 4-Anilido-l-phenetbyJpipendine, 485 4-Anilidopipendines, 466 4-Anilinopipendines, 287 4...

Spectroscopy And Other Physical Measurements

In this section a selection of studies relating to drug geometry, and having possible implications to pharmacological activity, has been included. Numerous studies characterizing products and establishing their stereochemistry may be found in publications relating to specific 4,5-epoxymor-phinan series. Twenty-two 4,5-epoxymorphinans related to ( )-morphine were the subject of a 60 MHz 'H-nmr study reported in 1964.(386) Assignments were made for most protons, but particular attention was paid...

N

45 Projection formula of reversed ester of pethidine significance of the orientation of the phenyl and piperidine rings in absolute terms is doubtful, however, since, as has been poinled out,(22) the corresponding value of the relatively weak and non stereoselective analgesic (+)- 3-allylprodine is also negative and within the range found for potent agents. Furthermore, activity differences between antipodal forms of the 3-2-methyl reversed ester cannot be accounted for in this manner because...

Basic Nitrogen And C14 Substituents

More detailed consideration will now be given to the influence of N- and C-14 ( C-11 inbenzomorphans) substituent structure upon the pharmacological profile of opoid ligands. The first N-substituted series to be examined in any detail was that of normorphines from which it emerged that antagonist properties were associated with a 3-carbon (mostly linear) N-substituent.(24' In this series propyl and allyl were ranked equipotent versus morphine while small branched chain (isoPr, 2-methylallyl)...

Lso

4-H Tesonance 84.4 ppm doublet (12.5 Hz) of triplets (5 Hz) (45 stereoisomer depicted) 84.53 ppm triplet (12.5 Hz) of doublets (4.5 Hz) pethidines and the related prodines (p. 260) in terms of not only relative geometry but probably also of absolute configuration. The configuration of (-)-cis 8 has been provisionally assigned as 3S, 4R and is seen to be equivalent to that of the more active antipode of 3-prodine (3R, 4S) when allowance is made for the RS stereochemical convention (see 9)....

Dielsalder Adducts Of Thebaine

A dramatic stimulus was given to synthetic opioid research in the early 1960s with a report by Bentley and Hardy(322) that compounds derived from the addition of dienophiles to thebaine gave analgesic potencies of extraordinary levels, up to almost 103 x morphine in the rat (RTF). The rationale for this approach was the view that if morphine and related compounds bound to receptors in order to initiate their responses, molecular flexibility would permit a molecule to adapt to a number of...

References

Rossi, and K. Hoffmann, Experientia 13, 400 (1957). 2. F. Gross and H. Turrian, Experientia 13, 401 (1957). 3. A. Hunger, J. Kebrle, A. Rossi, and K. Hoffmann, Helv. Chim. Acta 43, 800, 1032, 1046, 1298, 1727 (1960). 4. N. B. Eddy, Chem. Ind. (Lond.) 1462 (1959). 5. G. Bromig, Klin. Wschr. 36, 960 (1958). 6. G. A. Deneau, J. McCarthy and M. H. Seevers, Minutes 20th Meeting Committee on Drug Addiction and Narcotics, National Research Council, Washington, D.C., January...

Concluding Remarks

A consistent stereochemical structure-activity pattern may be built up on the basis of the 4-phenylpiperidine ligands associating with the opioid receptor in the form of equatorial 4-phenyl chair conformations. Other conformations (i.e., axial 4-phenyl chairs or flexible boat forms) could have been employed as the basic active species but greatest adherence to probable conformations is possible by the approach adopted furthermore, no need arises to assume a major difference in the binding modes...

Receptor Surface

Diagrammatic representation of the three-dimensional arrangement of morphine and the analgesic receptor site. The diagrams represent the lower surface of the drug and the upper surface of the receptor complementary surfaces in front of, behind, and in the plane of the paper are represented by , , and , respectively. This drawing is a modified form of the original diagram to take into account the true configuration of morphine, which was unknown (+)-morphine and the receptor are shown...

Aromatic Features

All active compounds possess at least one aromatic ring (see p. 75 for one minor exception). The most common aromatic entity is the phenyl ring as in pethidine (one ring) and methadone (two rings), while in morphine, the morphinans, and the benzomorphans a phenyl ring forms part of a polycyclic skeleton. Substituents in the benzene ring are generally disadvantageous, but a correctly placed hydroxy group (phenolic) is a requirement for high activity in morphine and its congeners while several...

Kappaagonists And Antagonists

As already mentioned, oxidation of C-l methylene of cyclazocine to carbonyl abolishes the antagonist but retains the agonist actions of the parent compound (p. 423). The behavioral and pharmacological effects of the oxidized product ketazocine 26a in the chronic spinal dog were subsequently compared with those of morphine by Martin, and as a result of differences observed, he dubbed the two compounds k- and -agonists, respectively.'106' Thus, while morphine induced analgesia, meiosis,...

Introduction

Simplification of the morphine structure to give series of morphinan congeners Chapter 3 demonstrated not only that strong analgesics with activities greater than that of morphine could be developed, but that accentuation of other opiate properties e.g., cough suppression could be selected. Further simplification to a bridged naphthalene, by exclusion of the morphinan D-ring, rather than a phenanthrene structure, was, therefore, an obvious progression. The chemistry of such bridged...

Oh

59 from isoneopine 58 , which was readily available from thebaine. ll7 The reaction sequence followed is outlined in Scheme 2.10. O-Demethylation of 59 to B C irans-morphine was effected by the diphenylphosphide anion. 118 Surprisingly, in view of the higher activity of B C irans-morphinans over their B C cis-counterparts p. 136 , B C irans-morphine exhibited a lower level of antinociceptive activity than did natural morphine. The obvious difference between the two structures is the presence...