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Opioid agonists with selectivity for mu, delta and kappa-receptors have each been shown to inhibit the K+-stimulated release of [3H]norepinephrine (NE) from slices of guinea pig cortex maintained in vitro. In order to provide further evidence that each of these types of opioid receptor can regulate the release of NE in this tissue, experiments with receptor-type selective opioid antagonists have been conducted. In initial experiments, the selectivity of the antagonists for specific types of opioid receptors in the cortex of the guinea pig in an incubation medium of the same composition as that used for release studies was confirmed. The delta-receptor selective antagonist, ICI 174,864, prevented the inhibitory actions of the delta-selective agonist, [D-Pen2,D-Pen5]enkephalin (DPDPE), but had little effect on the inhibitory actions of the mu-selective agonist, Tyr-D-Ala-Gly-MePhe-Gly-ol (DAMGO), or the kappa-selective agonist, U-50,488H. In contrast, the kappa-selective antagonist, nor-binaltorphimine (nor-BNI) prevented the inhibitory actions of U-50,488H, but had little effect on the inhibitory actions of DPDPE or DAMGO. The greater potency of the partially mu-selective antagonist, naloxone, in reversing the effects of DAMGO relative to those of DPDPE or U-50,488H was confirmed. These results support the conclusion that mu- delta- and kappa-opioid receptors each exert a negative regulatory effect on the stimulated release of NE in the cortex of the guinea pig.

In an effort to investigate whether "address" segments of endogenous opioid peptides, which are responsible for modulating receptor selectivity, also could modulate the selectivity of opioid alkaloid pharmacophores, we have synthesized analogues of leucine-enkephalin and dynorphin in which the N-terminal dipeptide "message" sequence has been replaced by oxymorphone or naltrexone. A hydrazone group was employed as a linkage between the alkaloids and peptides. The binding data for mu, kappa, and delta receptors indicate that peptide portions of the analogues can modulate the receptor selectivity of the attached alkaloid pharmacophores. The selectivity for different opioid receptor types depends on a balance between the affinities of the message and address components. In cases where these components have comparable receptor affinities, the address can significantly shift selectivity by increasing affinity to one receptor type while reducing affinity to other types. When the message component has high affinity for a particular receptor type, the modulatory role of the address is expressed mainly by reducing the affinity of the ligand for other opioid receptor types.

The effectiveness of phosphonamidate peptide analogues as inhibitors of rat kidney or human brain metalloendopeptidase (enkephalinase, E.C. 3.4.24.11) and angiotensin-converting enzyme (ACE, 3.4.14.1) has been explored with a series of enkephalin analogues in which the scissile Gly3-Phe4 amide bond has been replaced with a phosphonamidate moiety. These compounds exhibited good inhibitory potency against enkephalinase with several of the analogues having Ki values in the submicromolar range as contrasted to micromolar or higher toward ACE. Within a series of [(N-acylamino)methyl] phosphonamidates there was a dramatic decrease in inhibitory activity against enkephalinase as the N-acyl moiety was substituted with larger, more hydrophobic acyl groups. Likewise, the inhibitory activity of the [(N-acylamino)methyl] phosphonamidates against ACE was attenuated by larger phenylalkyl acyl functionalities, although not to the same degree as against enkephalinase. However, phosphonamidate pentapeptide analogues of (Leu)enkephalin and (D-Ala2,D-Leu5)enkephalin showed good inhibitory potency against both enzymes. Interestingly, these two (Leu)enkephalin phosphonamidate analogues were completely inactive in the electrically stimulated guinea pig ileum and mouse vas deferens preparations. Conformational factors that may be involved in this inactivity are discussed.

Enantiomers of beta-1,2-dimethyl-4-phenyl-4-(propionyloxy)piperidine (4) were employed as probes to demonstrate that opioid receptors are capable of distinguishing between the enantiotopic edges (the Ogston effect) of the piperidine ring. These enantiomers, (-)- and (+)-4.HCl, were prepared by esterification of the corresponding alcohols, (+)- and (-)-4a. Single crystal X-ray studies of (-)-4a.HCl reveal that it possesses the 2R,4S absolute configuration. Analgetic testing in mice (hot-plate) and receptor binding studies indicate that (-)-(2S,4R)-4.HCl is approximately ten times more potent than its enantiomer. The results are consistent with the operation of the Ogston effect in the interaction of achiral 4-phenylpiperidines with opioid receptors. Additionally, it is suggested that the piperidine ring of these and other closely related 4-phenylpiperidines bind within a receptor subsite cleft whose dimensions exclude diequatorial 2,6- and 3,5-dimethyl-substituted ligands.

In an effort to develop selective antagonists for kappa opioid receptors, bivalent ligands that contain opioid antagonist pharmacophores derived from naltrexone or other morphinans were synthesized and tested on the guinea pig ileum (GPI) and mouse vas deferens (MVD) preparations. The minimum requirements for kappa selectivity are at least one free phenolic OH group and one N-cyclopropyl or N-ally substituent. Several compounds (3, 8, 10) with kappa selectivity as good as or better than norbinaltorphimine (nor-BNI, 2) were discovered. The structure-activity relationship revealed that the pyrrole ring functions strictly as a spacer and does not contribute to kappa selectivity. The pharmacologic data suggest that only one antagonist pharmacophore may be required for kappa selectivity and that the other morphinan portion of the molecule confers selectivity by interacting with a unique subsite proximal to the antagonist pharmacophore recognition locus.

The concept of multiple opioid receptors and multiple modes of interaction with a single receptor emanated from two convergent lines of research. This proposal was based originally on a detailed analysis of a wide spectrum of structure-activity relationships among analgesic ligands (1, 2). Very soon, pharmacological studies complemented and provided a more detailed framework for this concept (3-5). More recently, the multiple receptor concept has been advanced through a number of in vitro and in vivo biological assays and the opioid receptor binding assay. Data from such studies have been summarized in a number of reviews (6-13). Based on a wide range of pharmacological tests in the chronic spinal dog, Martin and coworkers (14, 15) suggested the designation 1-'-, K, or IT for those receptors at which morphine, ketazocine, and SKF 10,047 (N-allyl­ normetazocine) respectively are postulated to interact. The notion of different receptors for morphine-like and ketazocineor nalorphine-like compounds has been strengthened by the use of the pA2 concept (16) both in vitro (17-19) and in vivo (5) and by various other testing methods in vivo (20-22). The 8 and E receptor through which the enkephalins and l3-endorphin respectively are thought to mediate their effects have been identified in vitro (19,23,24). Thea receptor in vivo has been implicated in a number of physiological functions

Chlornaltrexamine (CNA) produces ultralong-lasting (3--6 days) narcotic antagonism in mice and persistent stereospecific binding to rat-brain homogenate. Protection studies in mice suggest that CNA mediates its narcotic antagonist effects by interacting with the same receptors that are occupied by naloxone. A single icv dose of CNA also has been found to inhibit the development of physical dependence in mice for at least 3 days. These studies suggest that CNA exerts its sustained effects by selective covalent association with opioid receptors.

Using the δ-enriched mouse vas deferens and the κ-enriched guinea-pig ileal longitudinal muscle preparations, a large variety of so-called ‘μ, κ, δ and σ’ opioid agonists were tested for their μ, κ and δ properties. Buprenorphine and U50,488H appeared to be the most highly selective agonists for μ and κ opioid receptors, respectively. Most ligands identified as specific agonists are in fact only selective and appear to interact at more than one receptor type.

A reaction sequence is described to synthesize (R, S)-6-ditrideuteriomethylamino-4,4-diphenylheptan-3-one hydrochloride ( methadone-d6.HCl ) in 10.5% overall yield starting from dimethylamine-d6 hydrochloride. While methadone-d6.HCl had rather similar physicochemical properties compared to methadone.HCl in the solid phase, a divergent behaviour was observed in solution ( pKa, chromatographic and 13C-NMR data ). A higher basicity along with a more important hydrophilicity were observed for the d6-derivative. A 13C-NMR study showed significant differences in the 13C chemical shifts, which were attributed in part to the intrinsic nature of D itself and in part to a conformational perturbation. The longer duration of antinociceptive action, along with higher t1/2 and clearance, and the depression of the metabolic N-demethylation process were the only biological properties modified by the deuteration.

Summary Oxyphenbutazone was oxidized when incubated with acetone powder prepared from sheep vesicular gland microsomes or with lipoxygenase at pH 4 or 5. Oxidation also occurred at pH 8 or 9, if arachidonate or linoleate was added to either of the incubation mixtures. The oxygenated product was found to be identical with 4-hydroxyoxyphenbutazone, which was synthesized and analyzed by gas liquid chromatography and mass spectrometry. The oxygenated compound was not an inhibitor of prostaglandin biosynthesis.

The highly selective non-equilibrium mu-antagonist beta-funaltrexamine (beta-FNA) produced a maximal 20-fold shift in the IC50 for the mu-agonist morphine on the guinea-pig ileum preparation, whilst producing no significant change in the IC50 for the kappa-agonist ethylketazocine. On preparations pretreated with beta-FNA, the pA2 values for the interaction of morphine and ethylketazocine with naloxone were similar. These values were similar to the pA2 value for the interaction of ethylketazocine and naloxone determined on control tissues, but significantly different from the pA2 value for morphine-naloxone on control tissues, indicating that the agonist actions of morphine on preparations pretreated with high concentrations of beta-FNA are mediated by kappa-, rather than mu-receptor interaction. On the mouse vas deferens preparation, co-incubation with the highly selective delta-agonist Tyr-D-Ser-Gly-Phe-Leu-Thr (DSLET) and the non-selective non-equilibrium opiate antagonist beta-chlornaltrexamine (beta-CNA) resulted in marked inhibition of the agonist actions of morphine but had no effect upon the agonist actions of the delta-agonist leucine-enkephalin. The pA2 values for the interactions of naloxone with leucine-enkephalin and etorphine were unaltered by pretreatment with beta-CNA and DSLET. In similarly pretreated tissues, the agonist actions of ethylketazocine were markedly inhibited. It is concluded that manipulation of the guinea-pig ileum and mouse vas deferens preparations in the described manner results in assay systems that possess a largely homogeneous receptor population, and as such are valuable tools with which to evaluate opioid activity.

The fumaramate methyl ester derivatives of naltrexone (beta-FNA) and oxymorphone (beta-FOA) were both found to be reversible agonists on the guinea pig ileal longitudinal muscle preparation. In addition, beta-FNA possessed on irreversible antagonistic effect against morphine whereas beta-FOA had no such capacity. Analysis by pA2 values revealed that beta-FOA resembled pure agonists like morphine and enkephalin while beta-FNA resembled the mixed agonist-antagonists like nalorphine and pentazocine. The antagonism by beta-FNA was very selective in that it antagonized pure agonists but had little or no effect on the effects of either mixed agonist-antagonists, ethylketocyclazocine or other non-opiate-type agonists like norepinephrine.

Attempted N,N-dibenzoylation of aminomethanesulfonic acid results in CS bond cleavage, generating synthetically useful α-benzamidomethylating electrophiles. The importance of this observation in regard to the reported failures to prepare sulfonamide analogs of peptides is discussed.

Crystalline perchlorate salts of aziridinium ions derived from phenoxybenzamine and dibenamine were prepared. Both aziridinium ions were tested on the rat vas deferens and found to possess alpha-adrenergic potencies which were nearly identical with those of the parent compounds. The hydrolysis rates of phenoxybenzamine and dibenamine aziridinium ions (2a,b) in physiological medium were found to be 6.0 4 x 10(-4) and 8.35 x 10(-4) sec-1, respectively. The rates of cyclization of the parent amines to 2a and 2b in aqueous medium were 1.9 x 10(-2) and 7.2 x 10(-3) sec-1, respectively. The potencies and kinetic profiles indicate that the aziridinium ion is the only active species in alpha-adrenergic blockade. Moreover, differences in potency between phenoxybenzamine and dibenamine appear to be exclusively to a difference in receptor affinity rather than to a difference in intrinsic alkylating ability.

Three prostaglandin endoperoxide analogs that possess the 2,3-diazabicyclo[2.2.1]heptane skeleton were synthesized and evaluated for activity in human platelets and in the rat fundus. All three compounds were inactive in inhibiting or stimulating platelet aggregation. One compound possessed weak contracting activity on the rat fundus.

Chlornaltrexamine (beta-CNA) a selective, long-acting irreversible opiate antagonist inhibited the analgesia, hypothermia, hypothermia tolerance and physical dependence produced by delta 9-tetrahydrocannabinol (THC) in rats. The results suggest that there are some common features between cannabis and opiates and some actions of THC may be mediated by opioid related mechanisms in the central nervous system.

We synthesized fentanyl analogues that possess key groups common to the opioid peptides to investigate whether or not these two classes of compounds interact with common subsites on opioid receptors. The design of the analogues was based on the possibility of structural analogy between the two aromatic rings of fentanyl and the Tyr1 and Phe4 residues of the opioid peptides. The synthesized compounds showed very weak or no opioid activity as tested in the electrically stimulated longitudinal muscle of the guinea pig ileum or mouse vas deferens preparations. These results, together with those of reported studies, suggest that fentanyl and the opioid peptides interact with different subsites on either mu or sigma receptors. Studies using the irreversible mu opioid receptor antagonist, beta-funaltrexamine, indicate that fentanyl interacts preferentially with mu opioid receptors.

The crystal structure of the dihydrobromide heptahydrate of nor-binaltorphimine (17, 17′-bis(cyclopropylmethyl)-6,6′,7,7′-tetrahydro-4,5α: 4′,5′α-diepoxy-6,6′-imino[7,7′ bimorphinan]-3,3′,14,14′-tetraol)is presented. This structure is the first reported structure of a rigid bivalent opioid ligand. Two morphinan pharmacophores are connected by a rigid spacer, the pyrrole ring. The nor-binaltorphimine structure itself shows unique, high selectivity as a kappa opioid receptor antagonist. Crystal data: P 3 2 , Z = 3, a = b = 20.223 (4), c = 9.541(7) A, α = β = 90°, γ = 120°; R = 0.079 (1765 reflections, F obs > 1σ( F )).

La naltrexone subit une enolisation en milieu acide en conditions douces; ce meme compose conduit aisement, par une annelation de Robinson, a une epoxy-4,5 benzo-6,7morphinanone

The anti-anti isomer of naltrexonazine (1) was synthesized, and its configuration was confirmed by X-ray crystallography. The syn-anti isomer is readily converted to 1 under acidic conditions. The apparent equal receptor binding of 1 and syn-anti isomer indicates that isomerization of the azine moiety may take place under the conditions of biological evaluation. Two possible explanations for wash-resistant binding of 1 to opioid receptors are presented. The first possibility involves a noncovalent interaction of the ligand with the opioid receptor, and the second considers covalent binding by a receptor-based sulfhydryl group.

The brain levels of meperidine and three N-alkyl homologues were determined at equal analgetic iv doses in mice. The relative levels of the four compounds in brain were found to be closely proportional to their ED50 doses even though the compounds exhibit a wide range in partition coefficient and metabolic N-dealkylation. While lipid solubility and metabolism are undoubtedly important factors in the overall time-course brain levels, it appears that during the period of analgetic measurement (5-60 min after injection) these factors do not profoundly affect the relative brain levels because peak uptake occurs within the first 5 min after administration of the homologues. As a consequence, the observed ED50 potencies appear to provide a fair approximation of the relative receptor affinities of the four homologues. N-Dealkylation was observed as a major metabolic transformation by mouse liver in vivo for all four compounds, and the extent of this N-dealkylation was found to directly correspond to the rates of N-dealkylation by mouse liver homogenate seen in an earlier study.

Analogues of leucine-enkephalinamide containing N-terminal cis- or trans-4-(3-hydroxyphenyl)-4-methylpipecolic acid were prepared to examine the conformational requirements of the N-terminal tyrosyl residue in opioid activity. The diastereomeric amino acids were prepared and purified by semipreparative HPLC before incorporation into the peptide. Spectroscopic analysis based on proton nuclear Overhauser enhanced differential spectroscopy (NOEDS) allowed assignment of the cis and trans stereochemistry. Despite spatial analogy between the trans isomer 5 and leucine-enkephalinamide, it possessed neither opioid agonist nor antagonist activity in the guinea pig ileal longitudinal muscle (GPI) or mouse vas deferens (MVD) preparations. Possible explanations for this inactivity are discussed.

In a variety of laboratory animals as well as humans, pregnancy has been associated with an activation of a maternal opioid system(s) and with a concomitant elevation in the threshold for maternal responsiveness to aversive stimuli. This analgesia is mediated via the activation of spinal opiate receptors and does not require an intact peripheral opioid system(s). The recently developed κ-selective opioid antagonist, nor-binaltorphimine (nor-BNI), significantly reduces the threshold for reflexive jumping in response to electric foot shock when administered to the lumbar intrathecal (i.t.) space of pregnant rats (day 20 of gestation). In contrast, i.t. nor-BNI when administered to non-pregnant rats as well as systemic (i.p.) administration of an intrathecally effective dose of nor-BNI to pregnant rats is without effect on the jump thresholds. These data indicate that the κ-type of opiate receptor mediates, at least in part, the analgesia observed during gestation, thus providing an important physiological function for this receptor type.

The effects of beta-FNA, a highly selective and irreversible mu opioid receptor antagonist, in altering tumor response in A/Jax mice inoculated with S20Y cells were determined. Inoculation of neuroblastoma cells in control subjects resulted in 100% tumor incidence within 16 days, and mean and median survival times of 36 and 35 days, respectively, following tumor inoculation. Tumor incidence and survival times were comparable to controls for mice given chronic injections of 2 mg/kg and 10 mg/kg beta-FNA every 48 h beginning 2 days after tumor inoculation. Tumor growth was subnormal in the 10 mg/kg beta-FNA group. Both dosages of beta-FNA were found to block morphine-induced analgesia for 48 h. These results suggest that, in and by themselves, mu receptors selectively antagonized by beta-FNA do not play an important role in neuro-oncogenic events.

The nonequilibrium narcotic antagonist, chlornaltrexamine (CNA) was used to bind selectively and covalently pioid specific sites on brain membrane preparations. Selective binding of [ 3 H]CNA occured with a saturation maximum of 185 fmol/mg protein. Bound [ 3 H]CNA was extracted with Triton X-100, dialyzed against Brij 36T, precipitated with trichloroacetic acid and chromatographed on an ultrogel AcA 22 column. The elution profile suggests that this extract contains a minimum of four selective [ 3 H]CNA complexes. At least two of these complexes migrate in a single large peak. Column calibration showed that this peak eluted at 590,000 daltons. One of these specific [ 3 H]CNA complexes elutes at the elution volume of the column and is dialyzable. Finally, putative aggregate of these complexes elutes with the void volume.

A series of beta-funaltrexamine (2, beta-FNA) analogues (3-14) were synthesized that contain a variety of electrophilic groups attached at the 6 beta-position of the opiate. The opioid agonist and antagonist activities of these ligands were evaluated in the guinea pig ileum (GPI) and mouse vas deferens (MVD) in vitro assays. Several of the compounds behaved like beta-FNA in that they exhibited reversible agonist activity at kappa opioid receptors and irreversible antagonist activity at mu opioid receptors. The rank order of irreversible antagonism for a series of related Michael acceptors did not parallel their intrinsic chemical reactivity, confirming that the degree of covalent binding is in part dependent on the spatial disposition of the electrophilic center relative to the receptor nucleophile (secondary recognition). The maleimidoacetamide 8 behaved very differently from beta-FNA in that it exhibited considerably greater irreversible mu antagonism in MVD relative to the mu blockage in the GPI. This suggests that different proportions of mu receptor subtypes exist in the two tissues. Several of the agents tested, including some nonreactive control compounds, displayed an unusual type of persistent kappa agonist activity in the GPI. This activity, which was reversed by addition of naloxone, reappeared upon washing. Receptor models have been presented to explain this effect. A few of the reactive ligands displayed a true nonreversible kappa agonist activity, suggesting a covalent association with the receptor. Of note in this regard was the propiolamide 6, which appeared to be an irreversible mixed agonist-antagonist at kappa and mu receptors.

In the guinea pig ileum preparation, naltrexone was 3.5 to 5 times more potent than naloxone in antagonizing morphine but the antagonists were equipotent in antagonizing ethylketazocine. In the mouse vas deferens preparation, naltrexone and naloxone were equipotent in antagonizing both morphine and [D-Ala2-D-Leu5]enkephalin. The data provide evidence that the naltrexone-reversible mu population of receptors in the guinea pig ileum are different from those in the mouse vas deferens. These findings also point out the uniqueness of the mu receptor system in the guinea pig ileum which is reflected by the potency differences between naltrexone and naloxone.

The synthesis of racemic threo- and erythro-5-methylmethadone (3a and 3b, respectively) was carried out and the solution conformation of each isomer was investigated through pKa and NMR studies. The data indicate that 3a-HCl exists exclusively in an internally hydrogen-bonded conformation while the erythro isomer 3b-HCl is present as a mixture of conformations. The erythro racemate 3b was found to possess 5.4 times the analgetic potency of (+/-)-methadone in contrast to the threo racemate 3a which was inactive and devoid of antagonist activity. The fact that the inactive racemate 3a contains the 5S,6R stereoisomer, which combines the configurations found in the more active enantiomers of methadone and isomethadone, suggests that the chiral centers do not behave as independent units and that conformational factors are playing an important role in governing stereoselectivity. These results, when analyzed together with earlier reports, suggest that one of the pharmacophoric conformations of the diphenylpropylamine analgetics possesses an antiperiplanar-like disposition of the Ph2CCOEt and +NHMe2 groups.

beta-Chlornaltrexamine and beta-funaltrexamine analogues 4-7 with different length "arms" to which an electrophilic moiety is attached were synthesized in an effort to obtain affinity labels that would selectively and irreversibly block specific opioid receptor types and subtypes. One of the compounds, 4, was a potent, irreversible blocker of opioid receptors in the guinea pig ileum and mouse vas deferens preparations. The results of this study suggest that nucleophiles that are remote from the recognition locus are capable of alkylation by reactive electrophiles.

Opical antipodes of the axial phenyl analgetic, alpha-promedol hydrochloride (3), were prepared and the absolute stereochemistry wasd determined by relating one of the enantiomers to its gamme diastereomer having the 2S, 4S,5R configuration. The analegetic potency of (+)-(2R,4S,5S)-3 is 20 times that of morphine, while its enantiomer, (-)-(2S,4R,5R)-3, is inactive at 50 mg/kg. These results are in accord with prior reports which indicate that substitution of a 3-or 5-alkyl group on the pro-4S enantiotopic edge of the piperidine ring leads to enantiomers which have greater potency than those substituted in an identical position on the pro-4R edge. This coupled with the fact that the torsion angle between the axial phenyl group and piperidine ring in (+)-3 is of the same sign as its equatorial congeners, suggests that the C(3)-C(4)-C(5) moiety and its substituents at C(4) are located in a similar chiral environment on the receptor. In contrast, the C(2)-N-C(6) portion of the axial and equatorial molecules does not bind in the same receptor environment, and it is suggested that different modes of interaction in the prodine series arise from different orientations of this moiety.

The α-cyanation of tertiary amines is customarily accomplished by mercuric acetate oxidation of the amine to form the enamine, which on treatment with base yields the corresponding Schiff's base. Subsequent treatment with aqueous potassium cyanide yields the desired product2. Alternatively, and less commonly, the α-cyanation of tertiary amines can be carried out electrolytically3,4

The relative reactivities of a number of alpha, beta-unsaturated ketones used as flavourings were determined using glutathione as the nucleophile. Monosubstitution at the beta-position of the alpha, beta-unsaturated system impeded nucleophilic addition by approximately 1000 times. Beta-Disubstitution reduced reactivity by more than 100,000 times. Endocyclic alpha, beta-unsaturated ketones were generally less reactive than alicyclic analogues. By way of comparison, the most reactive flavouring investigated, 2-octene-4-one, was consumed by glutathione about 700 times less rapidly than was methylvinyl ketone. Methylvinyl ketone was found to condense with guanylic acid 240,000 times more slowly than with glutathione. It is concluded that alpha, beta-unsaturated ketones used as flavourings generally possess low electrophilicity.

Pyrolytic cyclization of a- and β-methadol methiodides afforded cis and trans isomers of 2-ethyl-3,3-diphenyl-5-methyltetrahydrofuran, respectively. Catalytic hydrogenation of 2-ethyli-dene-3,3-diphenyl-5-methyltetrahydrofuran yielded the cis and trans isomers in a 2:1 ratio. The nmr spectra of these and structurally related compounds have been analyzed in terms of a half-chair conformation for 2-ethyl-5-methyl, 2-ethyl, and 5-methyl derivatives. An envelope conformation has been suggested for the compounds containing a double bond at C-2.

The synthesis of chiral exo and endo 5-sulbstituted N-losyl-2-azabicyclo[2.2.1]heptanes is reported. The nearly identical exo-endo equilibrium ratios of the title compounds and the carbocyclic analogs suggest that their geometries and sterie interactions are quite similar.

A facile route to 6-substituted 2-azabicyclo[2.2.1]heptanes via the novel tricyclic system, 2-azatricyclo[2.2.1.0 1,6 ]heptane ( 2 ), is described. The key intermediate ( 2 ) was prepared by oxidation of 4-aminomethylcyclopentene with lead tetra-acetate, and the bicyclic system was obtained by reaction of acetate with 2.MeI . Equilibration of exo - and endo -6-hydroxy-1-methyl-2-azabicyclo[2.2.1]heptane afforded an exo-endo isomeric ratio close to that of norborneol, and on this basis it is suggested that the steric requirements of the nitrogen lone pair are similar to that of CH.

The absolute configuration of certain (−)- N -[2-(phenalkylmethylamino)propyl]-propionanilides has been determined by relating them to D -(−)-alanine. The compounds corresponding to the L -configuration have greater analgesic potency than those with the D-configuration. An interpretation of the significance of the relationship of absolute configuration to analgesic activity is discussed in terms of an analgesic receptor surface.

The novel bicyclic system, N-tosyl-2-thia-5-azabicyclo[2.2.1]heptane (IV), was synthesized from tritosylhydroxy- L -prolinol and thioacetate anion. Sodium metaperiodate oxidation of (IV) yielded exclusively the exo sulfoxide (VI) from which the isomeric endo product (VIII) was obtained by treatment with ethyloxonium fluoroborate. Thermally induced equilibration studies demonstrated that the exo -oxide is thermodynamically more stable than the endo -oude. The sulfone (V) was prepared by oxidation with H 2 O 2 . The identity of all proton resonances in the 100-MHz NMR spectra of (IV–VI, VIII) were deduced from spin-decoupling experiments.