Acid-mediated ring-expansion reaction of N-aryl-2-vinylazetidines: synthesis and unanticipated reactivity of tetrahydrobenzazocines.

The aza-Clasen rearrangement of N-aryl-2-vinylazetidines has been explored. N-Aryl-2-vinylazetidines were transformed to corresponding tetrahydrobenzazocines in good yields. Unexpectedly, the tetrahydrobenzazocine was unstable and readily isomerized to vinyltetrahydroquinoline in the presence of acid. The mechanism of this ring contraction was studied in detail.

Redefining the structure-activity relationships of 2,6-methano-3-benzazocines. Part 8. High affinity ligands for opioid receptors in the picomolar Ki range: oxygenated N-(2-[1,1'-biphenyl]-4-ylethyl) analogues of 8-CAC.

N-[2-(4'-methoxy[1,1'-biphenyl]-4-yl)ethyl]-8-CAC (1) is a high affinity (K(i)=0.084 nM) ligand for the µ opioid receptor and served as the lead compound for this study. Analogues of 1 were made in hopes of identifying an SAR within a series of oxygenated (distal) phenyl derivatives. A number of new analogues were made having single-digit pM affinity for the µ receptor. The most potent was the 3',4'-methylenedioxy analogue 18 (K(i)=1.6 pM).

A novel synthesis of (di)-benzazocinones via an endocyclic N-acyliminium ion cyclisation.

The triflic acid-mediated endocyclic N-acyliminium ion cyclisation provides a facile synthesis of (di)-benzazocinones. On reduction of the 10-phenyl derivative, an unusually non-polar tertiary alkylamine was obtained.

Redefining the structure-activity relationships of 2,6-methano-3-benzazocines. Part 7: syntheses and opioid receptor properties of cyclic variants of cyclazocine.

A series of 7,8- and 8,9-fused triazole and imidazole analogues of cyclazocine have been made and characterized in opioid receptor binding and [(35)S]GTPgammaS assays. Target compounds were designed to explore the SAR surrounding our lead molecule for this study, namely the 8,9-fused pyrrolo analogue 2 of cyclazocine. Compared to 2, many of the new compounds in this study displayed very high affinity for opioid receptors.

Redefining the structure-activity relationships of 2,6-methano-3-benzazocines. Part 6: Opioid receptor binding properties of cyclic variants of 8-carboxamidocyclazocine.

A series of 7,8- and 8,9-fused pyrimidinone, aminopyrimidine and pyridone derivatives of 8-carboxamidocyclazocine (8-CAC) have been prepared and evaluated in opioid receptor binding assays. Targets were designed to corroborate a pharmacophore hypothesis regarding the bioactive conformation of the carboxamide of 8-CAC. In addition to the results from this study strongly supporting this pharmacophore hypothesis, a number of novel compounds with high affinity to opioid receptors have been identified.

Redefining the structure-activity relationships of 2,6-methano-3-benzazocines. 4. Opioid receptor binding properties of 8-[N-(4'-phenyl)-phenethyl)carboxamido] analogues of cyclazocine and ethylketocycalzocine.

The synthesis and evaluation of a series of aryl-containing N-monosubstituted analogues of the lead compound 8-carboxamidocyclazocine were performed to probe a putative hydrophobic binding pocket of opioid receptors. High binding affinity to mu, kappa, and delta opioid receptors was observed for the 8-[N-(4'-phenyl)-phenethyl)carboxamido] analogue.

Synthesis, stereochemistry, and analgesic activity of 4-mono- and 4,4-disubstituted 1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocines.

The synthesis of 4-alkyl-, 4-aralkyl-, and 4-alkenyl-1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocines is described together with some 4,4-disubstituted and 8-hydroxy derivatives. Evidence of the stereochemistry of the 4-substituent was from 1H and 13C NMR. In the 4-methyl series the equatorial epimer 1b has a higher analgesic (hot-plate) potency than 1a, and 10a, 10c, and 10f are also good agonists. 5a afforded analgesic properties without an antagonist component. Surprisingly 10d, bearing an 8-OH function, was without analgesic activity, contrasting with the significant hot-plate activity exhibited by 1,2,3,4,5,6-hexahydro-3,5,6-trimethyl-2,6-methano-3-benzazocine. If the assumption is made that the more active enantiomorph in members of this series is configurationally related to (-)-morphine, then it may be that the enantiotopic edge in hexahydro-2,6-methano-3-benzazocines has a narrow steric requirement for analgesic responses.

Synthesis and pharmacological properties of 1,2,3,4,5,6-hexahydro-1,6-methano-2-benzazocines.

1,2,3,4,5,6-Hexahydro-1,6-methano-2-benzazocine, 2'-methoxy-1,2,3,4,5,6-hexahydro-1,6-methano-2-benzazocine, and N-alkyl derivatives of 2'-hydroxy-1,2,3,4,5,6-hexahydro-1,6-methano-2-benzazocine have been synthesized in order to evaluate their analgesic activities. These compounds show only slight antinociceptive activities in the mouse hot-plate assay.

Synthesis of (+)-cis-N-(4-isothiocyanatobenzyl)-N-normetazocine, an isothiocyanate derivative of N-benzylnormetazocine as acylant agent for the sigma(1) receptor.

(+)-cis-N-(4-Isothiocyanatobenzyl)-N-normetazocine (BNIT) (+)-(4) was designed and synthesized as a derivative of the potent and selective sigma(1) receptor ligand (+)-cis-N-benzyl-N-normetazocine for irreversibly blocking sigma(1) binding sites. Pretreatment of guinea pig brain membranes with BNIT (0.1, 1, and 5 microM) caused a concentration-dependent loss of binding of the selective sigma(1) ligand [(3)H]-(+)-pentazocine. Binding experiments with [(3)H]-1,3-di(2-tolyl)guanidine ([(3)H]-DTG), a ligand of sigma(1) and sigma(2) receptors, showed that pretreatment with BNIT blocked only the sigma(1) component of [(3)H]-DTG binding.

Synthesis and sigma binding properties of 1'- and 3'-halo- and 1',3'-dihalo-N-normetazocine analogues.

The synthesis and sigma 1 and sigma 2 binding properties of several 1'- and 3'-halo- and 1',3'-dihalo-substituted analogues of (+)-N-benzyl- and (+)- and (-)-N-dimethylallyl-N-normetazocine are presented. Structure-activity relationship analyses of the binding data showed that halogen substitution at the 1'-position of these N-substituted N-normetazocine analogues had little effect on sigma 1 binding affinity, whereas 3'-halo substitution as well as 1',3'-dihalo substitution resulted in a reduction of affinity. sigma 2 affinity was increased by the presence of a 3'-bromo substituent in this series of (+)-N-substituted N-normetazocines.

Non-peptide ligands for opioid receptors. Design of kappa-specific agonists.

A series of phenyl carboxyl esters 5a-d derived from N-(cyclopropylmethyl)normetazocine was synthesized and evaluated for its selectivity at mu, kappa, and delta opioid receptors. Compound 5a, although 43 times less potent than the reference compound U50488, was specific for kappa receptors, having no detectable affinity for either mu or delta receptors. Greater binding affinity was seen with the diastereoisomer having the 1'R,2'S stereochemistry in the cyclopropyl ring of the nitrogen substituent, which was only 12 times less active than U50488. Antinociceptive activity in the mouse tail flick was only slightly lower than that of U50488 (ED50 = 7.66 vs 4.52 mg/kg). Naloxone fully prevented antinociception induced by (1'R,2'S)-5a at the doses of 2.0 mg/kg. Compound (1'R,2'S)-5a is one of the most kappa-selective non-peptide compounds reported to date. The implications of these results in terms of requirements for kappa ligands are discussed.

Synthesis and pharmacological evaluation of potent and enantioselective sigma 1, and sigma 2 ligands.

In a previous study we found that substitutions of the (+)-cis-N-normetazocine nucleus of (+)-MPCB with 1-adamantanamine provide the compound (+/-)-10 with high affinity and selectivity for sigma receptors. Starting with this result we have synthesized a new series of eight 1-phenyl-2-cyclopropylmethylamines structurally related to (+/-)-10, and binding affinities, with respect to sigma 1, sigma 2, opioid and dopaminergic D2 receptors, have been reported. All compounds showed a negligible opioid and dopaminergic affinity and high selectivity for sigma receptors. Modifications on the amino moiety and methylcarboxyester group of 10 provide compounds with different sigma 1 and sigma 2 binding affinity and selectivity. Moreover, we have also synthesized the respective enantiomers of componds (+/-)-10 and (+/-)-18 in order to evaluate the enantioselectivity for sigma 1 and sigma 2 receptors. The binding data showed that carboxymethylester on the cyclopropane ring was more critical for enantioselectivity than the hydroxymethylenic group. In fact, the (-)-10 enantiomer showed a preference for sigma 1 whereas (+)-10 showed a preference for sigma 2.

Asymmetric syntheses of (-)-pentazocine and (-)-eptazocine through an aza-Prins cyclization.

Two down more to go: The asymmetric syntheses of (-)-pentazocine and (-)-eptazocine are presented. The highlights of the syntheses are the construction of the core skeleton through an aza-Prins cyclization and intramolecular Friedel-Crafts reaction.

No-carrier-added (NCA) (+/-)-N-(3-[18F]fluoropropyl)-N-normetazocine-synthesis and PET studies in a baboon.

No-carrier-added (NCA) (+/-)-N-(3-[18F]Fluoropropyl)-N-normetazocine (2) was synthesized by N-alkylation of (+/-)-N-normetazocine (1) with NCA 1-[18F]fluoro-3-iodopropane in an overall radiochemical yield of 10% (EOB) with a mass of 3.5 nmol in a synthesis time of 90 min from end of bombardment (EOB). PET studies of 2 in a baboon did not indicate specificity for opiate receptor sites alone: The activity declined rapidly in the striatum, the frontal cortex and the cerebellum. The baboon total arterial plasma radioactivity clearance was very rapid and the metabolism of compound 2 in plasma was also very rapid. These results suggest that compound 2 is not a suitable radioligand for imaging opiate receptors in the human brain by positron tomography.

Redefining the structure-activity relationships of 2,6-methano-3-benzazocines. Part 2: 8-formamidocyclazocine analogues.

High affinity binding for mu and kappa opioid receptors has been observed in analogues of cyclazocine, ethylketocyclazocine and naltrexone where the prototypic (of opiates) phenolic OH group was replaced with a formamide (-NHCHO) group. For the 8-formamide analogue of cyclazocine, binding is highly enantiospecific (eudismic ratios approximately 2000 for mu and kappa) with K(i) values

8-Carboxamidocyclazocine: a long-acting, novel benzomorphan.

To obtain benzomorphans with a longer duration of action that may be potential therapeutics for treating cocaine abuse, 8-carboxamidocyclazocine was synthesized. The pharmacological properties of 8-carboxamidocyclazocine were compared with the parent compound cyclazocine. Changing the 8-hydroxyl group on cyclazocine to an 8-carboxamido group resulted in only a 2-fold decrease in the affinity of the compound for the kappa-receptor, and no change in the affinity for the mu-opioid receptor, with both compounds having K(i) values of less than 1 nM, based on radioligand binding assays. In the guanosine 5'-O -(3-[(35)S]thio)triphosphate ([(35)S]GTPgammaS) binding assay, the two compounds produced moderate stimulation of GTP binding to the human kappa- and mu-receptors. When given by i.c.v. injection, the compounds produced less than 60% antinociception in the mouse 55 degrees C warm-water tail-flick test. However, in the mouse writhing test, the compounds had high potency in producing antinociception. Antinociception induced by either 8-carboxamidocyclazocine or cyclazocine was mediated by both kappa- and mu-opioid receptors. Cyclazocine acted as a mu-antagonist in addition to its agonist properties at the mu-receptor, as measured by the inhibition of morphine-induced antinociception. In contrast, 8-carboxamidocyclazocine did not inhibit morphine-induced antinociception, demonstrating that it was not a mu-opioid receptor antagonist in this assay. An i.p. injection of an ED(70) dose of 8-carboxamidocyclazocine produced antinociception that lasted for 15 h in contrast to cyclazocine, which produced antinociception, lasting 2 h. 8-Carboxamidocyclazocine is a novel, long-acting benzomorphan, which possesses pharmacological properties that are distinct from the properties of cyclazocine.