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Surprisingly, a methyl group j3- to nitrogen is superior to an a-placement in basic amides 13 related to methadone, made by treating appropriate acid chlorides with a secondary amine. Table 9.1 shows data for some amides derived from pyrrolidine. The morpholine group confers highest potencies in this series, while in the 3-methyl derivatives, activity resides mainly in the'(+) isomer. Dextromoramide (R-875, Palfium, Jetrium) is especially potent, being 20-40 times more active than morphine in...

References

1 E C Kleiderer, J B Rice, V Conquest, and J H Williams, Report No PP 981, Office of the Publication Board, Depart of Commerce, Washington, D C (1945) 2 J E Denton and H K Beecher, J Am Med Assoc 141, 1146 (1949) 3 A J H Hewer and C A Keele, Lancet 255, 683 (1948) 4 E A Gaensler, J Clin Invest 30, 406 (1951) 5 E Kutter, A Herz, H J Teschemacher, and R Hess, J Med Chem 13, 801 (1970) 6 Martindale, The Extra Pharmacopoeia, 28th ed , p 1015, The Pharmaceutical Press, London (1982) 7 N B Eddy, H...

Summary Of Structureactivity Relationships

Throughout this chapter reference has been made to criteria necessary for activity in each substituted series. In this summary our aim will be to highlight those parameters that appear to be necessary for maximizing, or more realistically, optimizing, opioid actions. Various aspects of structure activity relationships in 4,5-epoxymorphinans have been reviewed,'201'461467' and specific consideration has been given to quantum chemical studies with particular reference to polar group...

Structureactivity Relationships

A veritable host of methadone-related structures has been investigated and the resultant structure-activity data are conveniently discussed (with some inevitable overlap) under the subdivisions of changes in (1) the basic gfoup, (2) the NCCCPh2 chain, (3) the oxygen function, and (4) the aromatic groups. 1. Variation of the basic group of methadone has led to the morpholino (11a, phenadoxone, Heptalgin) and piperidino (lib, dipipanone, Pipadone) 11 RCHMeCH2CPh2COEt a R l > b R l analogs, both...

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...

Synthesis

Kametani< 23) in 1977 reviewed the total synthesis of isoquinoline alkaloids, including alkaloids of the morphine series. The first complete synthesis of ( )-morphine was achieved by Gates and his co-workers(4'5) in the early 1950s, although prior to that, morphinan and isomorphinan structures had been prepared.24,25 Gates required the 4-cyanomethyl-l,2-naphthoquinone, 4 (Scheme 2.1), which is capable of undergoing Diels-Alder addition of butadiene to the partially saturated phenan-threne, 5....

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...

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...

N-phenethylnordesomorphine Synthesis

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...