Search

(+)-(2 S ,6 S ,11 S )- and (-)-(2 R ,6 R ,11 R )-Benzomorphan derivatives have a different binding affinity for sigma-1 (σ1R) and opioid receptors, respectively. In this study, we describe the synthesis of the (+)-enantiomer [(+)-LP1] of the benzomorphan MOR agonist/DOR antagonist LP1 [(-)-LP1]. The binding affinity of both (+)-LP1 and (-)-LP1 for σ1R and sigma-2 receptor (σ2R) was tested. Moreover, (+)-LP1 opioid receptor binding affinity was also investigated. Finally, (+)-LP1 was tested in a mouse model of inflammatory pain. Our results showed a nanomolar σ1R and binding affinity for (+)-LP1. Both (+)-LP1 and (-)-LP1 elicited a significant analgesic effect in a formalin test. Differently from (-)-LP1, the analgesic effect of (+)-LP1 was not reversed by naloxone, suggesting a σ1R antagonist profile. Furthermore, σ1R agonist PRE-084 was able to unmask the σ1R antagonistic component of the benzomorphan compound. (+)-LP1 could constitute an useful lead compound to develop new analgesics based on mechanisms of action alternative to opioid receptor activation.

The pivotal role of the stereocenter at the N-substituent of the 6,7-benzomorphan scaffold was investigated combining synthetic and pharmacological approaches. 2R- and 2S-diastereoisomers of the multitarget MOR/DOR antinociceptive ligand LP2 (1) were synthesized and their pharmacological profile was evaluated in in vitro and vivo assays. From our results, 2S-LP2 (5) showed an improved pharmacological profile in comparison to LP2 (1) and 2R-LP2 (4). 2S-LP2 (5) elicited an antinociceptive effect with a 1.5- and 3-times higher potency than LP2 (1) and R-antipode (4), respectively. In vivo effect of 2S-LP2 (5) was consistent with the improved MOR/DOR efficacy profile assessed by radioligand binding assay, to evaluate the opioid receptor affinity, and BRET assay, to evaluate the capability to promote receptor/G-protein and receptor/β-arrestin 2 interaction. 2S-LP2 (5) was able to activate, with different efficacy, G-protein pathway over β-arrestin 2, behaving as biased agonist at MOR and mainly at DOR. Considering the therapeutic potential of both multitarget MOR/DOR agonism and functional selectivity over G-protein, the 2S-LP2 (5) biased multitarget MOR/DOR agonist could provide a safer treatment opportunity., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)

Despite the fact that the benzomorphan skeleton has mainly been employed in medicinal chemistry for the development of opioid analgesics, it is a versatile structure. Its stereochemistry, as well as opportune modifications at the phenolic hydroxyl group and at the basic nitrogen, play a pivotal role addressing the benzomorphan-based compounds to a specific target. In this review, we describe the structure activity-relationships (SARs) of benzomorphan-based compounds acting at sigma 1 receptor (σ1R), sigma 2 receptor (σ2R), voltage-dependent sodium channel, N-Methyl-d-Aspartate (NMDA) receptor-channel complex and other targets. Collectively, the SARs data have highlighted that the benzomorphan nucleus could be regarded as a useful template for the synthesis of drug candidates for different targets., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

The opioid pharmacological profile of cis -(-)- N -normetazocine derivatives is deeply affected by the nature of their N -substituents. Here, our efforts were focused on the synthesis and pharmacological evaluation of novel derivatives of the lead LP1, a multitarget opioid analgesic compound featuring an N -phenylpropanamido substituent. LP1 derivatives 5a - d and 6a - d were characterized by flexible groups at the N -substituent that allow them to reposition themselves relative to cis -(-)- N -normetazocine nucleus, thus producing different pharmacological profiles at the mu, delta and kappa opioid receptors (MOR, DOR and KOR) in in vitro and in vivo assays. Among the series, compound 5c , with the best in vitro and in vivo profile, resulted a MOR agonist which displays a K i MOR of 6.1 nM in a competitive binding assay, and an IC 50 value of 11.5 nM and an I max of 72% in measurement of cAMP accumulation in HEK293 cells stably expressing MOR, with a slight lower efficacy than LP1. Moreover, in a mouse model of acute thermal nociception, compound 5c, intraperitoneally administered, exhibits naloxone-reversed antinociceptive properties with an ED 50 of 4.33 mg/kg. These results expand our understanding of the importance of N -substituent structural variations in the opioid receptor profile of cis -(-)- N -normetazocine derivatives and identify a new MOR agonist useful for the development of novel opioid analgesics for pain treatment., Competing Interests: The authors declare no conflict of interest.

The hypothesis that central analgesia with reduced side effects is obtainable by occupying an 'allosteric' site in the MOR ligand binding domain requires the development of new ligands with peculiar pharmacological profile to be used as tools. New benzomorphan derivatives, analogues of LP1, a multitarget MOR agonist/DOR antagonist, were designed to examine in depth MOR ligand binding domain. Compound 5, bearing a diphenylic N-substituent on the benzomorphan nucleus, showed an affinity (K i μ =0.5±0.2nM) comparable to that of LP1 and a better selectivity versus DOR and KOR. It elicits antinociceptive effects in ex vivo (GPI) and in vivo. This new compound engages receptor amino acidic residues not reached by LP1 and by other established MOR ligands. Molecular modeling studies, conducted on 5 and on several reference compounds, allowed us to propose possible residues in the MOR ligand binding domain essential for their interactions with 'orthosteric' and 'allosteric' binding sites., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

A novel structural class with high affinity and subtype selectivity for the sigma 2 receptor has been discovered. Preliminary structure-affinity relationship data are presented showing that 8-substituted 1,3,4,5-tetrahydro-1,5-methanobenzazepine (norbenzomorphan) derivatives elicit modest to high selectivity for the sigma 2 over the sigma 1 receptor subtype. Indeed, piperazine analogue 8-(4-(3-ethoxy-3-oxopropyl)piperazin-1-yl)-1,3,4,5-tetrahydro-1,5-methanobenzazepine-2-carboxylate (SAS-1121) is 574-fold selective for the sigma 2 over the sigma 1 receptor, thereby establishing it as one of the more subtype-selective sigma 2 binding ligands reported to date. Emerging evidence has implicated the sigma 2 receptor in multiple health disorders, so the drug-like characteristics of many of the selective sigma 2 receptor ligands disclosed herein, coupled with their structural similarity to frameworks found in known drugs, suggest that norbenzomorphan analogues may be promising candidates for further development into drug leads., (© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

A 124-member norbenzomorphan library has been prepared utilizing a novel multicomponent assembly process (MCAP) followed by a variety of ring-closing reactions to generate norbenzomorphan scaffolds that were readily derivatized via a series of aryl halide cross-coupling and nitrogen functionalization reactions. Biological screening has revealed some novel activities that have not been previously associated with this class of compounds.

N-p-Toluenesulfonyl (Ts) aldimines reacted with 3-ethoxycyclobutanones by catalysis of titanium(IV) chloride to afford 2,3-di- or 2,3,3-trisubstituted N-Ts-2,3-dihydro-4-pyridones. Synthesis of (+/-)-bremazocine was efficiently accomplished by using this method.

6,7-benzomorphan derivatives, exhibiting different mu, delta, and kappa receptor selectivity profiles depending on the N-substituent, represent a useful skeleton for the synthesis of new and better analgesic agents. In this work, an aromatic ring and/or alkyl residues have been used with an N-propanamide or N-acetamide spacer for the synthesis of a new series of 5,9-dimethyl-2'-hydroxy-6,7-benzomorphan derivatives (12-22). Data obtained by competition binding assays showed that the mu opioid receptor seems to prefer an interaction with the 6,7-benzomorphan ligands having an N-substituent with a propanamide spacer and less hindered amide. Highly stringent features are required for delta receptor interaction, while an N-acetamide spacer and/or bulkier amide could preferentially lead to kappa receptor selectivity. In the propanamide series, compound 12 (named LP1) displayed high mu affinity (Ki=0.83 nM), good delta affinity (Ki=29 nM) and low affinity for the kappa receptor (Ki=110 nM), with a selectivity ratio delta/mu and kappa/mu of 35.1 and 132.5, respectively. Further, in the adenylyl cyclase assay, LP1 displayed a mu/delta agonist profile, with IC50 values of 4.8 and 12 nM at the mu and delta receptors, respectively. The antinociceptive potency of LP1 in the tail-flick test after sc administration in rat was comparable with the potency of morphine (ED50=2.03 and 2.7 mg/kg, respectively), and was totally reversed by naloxone. LP1, possessing a mu/delta agonist profile, could represent a lead in further developing benzomorphan-based ligands with potent in vivo analgesic activity and a reduced tendency to induce side effects., (Copyright (c) 2010 Elsevier Ltd. All rights reserved.)

A series of aminothiazole-derived morphinans, benzomorphans, and morphine were synthesized. Although their affinities were somewhat lower than their phenol prototypes, one compound (9a, ATPM) has been identified possessing high affinity and selectivity at the kappa receptor. Functional assays showed that 9a was a full kappa but partial mu agonist; the efficacy at kappa was significantly greater than at mu receptors. This novel compound may be valuable for the development of long-acting analgesics and drug abuse medication.

In order to provide ready access to multigram quantities of the optically pure bremazocines [(-)- and (+)-9,9-dimethyl-5-ethyl-2-hydroxy-2-(1-hydroxy-cyclopropylmethyl)-6,7-benzomorphan)], we have developed an improved non-chromatographic synthesis, and determined the optical purity of their N-nor precursors using a rapid and relatively simple 1H NMR method based on diastereomeric derivatization with optically pure 1-phenylethylisocyanate. This method of determining optical purity should be readily amenable to similar systems containing phenolic amino functionalities. Finally, a greatly simplified methodology for introduction of the N-(1-hydroxycyclopropylmethyl) substituent in bremazocine is described. The improved synthetic method-the overall yield was increased about 3-fold-combined with the practical methodology to determine optical purity will considerably facilitate the employment of these enantiomers as pharmacological tools for examination of the kappa-opioid receptor system, as well as their evaluation as drug abuse treatment agents. This synthesis will also enable the study of these enantiomers for other, non-classical applications (e.g., treatment agents for HIV).

Aim: To design and synthesize new chiral 8-(substituted) amino-analogues of 3-[(tetrahydro-2-furanyl)methyl] benzomorphans, to expand knowledge of the structure-activity relationship (SAR) for 8-aminobenzomorphan., Methods: Target compounds were synthesized from the 8-triflate of the optically active 3-[(tetrahydro-2-furanyl)methyl]-2,6-methano-benzomorphans using Pd-catalyzed aminations. Opioid receptor binding experiments were performed to evaluate their biological activities., Results: Both 8-amino and 8-phenylamino analogues showed lower binding affinity for mu, delta and kappa receptors than corresponding 8-hydroxy-3-[(tetrahydro-2-furanyl)methyl]-2,6-methano-benzomorphan in vitro., Conclusion: The relative poor binding affinity of the target compounds did not warrant conducting the in vivo studies to determine if they have the profile(kappa agonist/mu antagonist) that will be potentially useful in the treatment of drug addiction. Further study is in progress.

We describe a highly efficient, general strategy for the enantioselective synthesis of benzomorphans (45-46% overall yield from commercially available material). The new synthesis demonstrates the effectiveness of an unprecedented diastereoselective cycloisomerization via migratory hydroamination and the power of palladium-catalyzed asymmetric allylic alkylation (AAA) of simple ketone enolates in the context of complex synthesis. The strategy outlined here for the enantioselective synthesis of three contiguous stereogenic centers and the novel cycloisomerization should have many applications in alkaloid synthesis.

We have synthesized a series of 6,7-benzomorphan derivatives and determined their ability to bind to voltage-dependent sodium channels. We have also compared the functional consequences of this blockade in vitro and in vivo. The ability of the compounds to displace [(3)H]batrachotoxin from voltage-dependent sodium channels was compared with their ability to inhibit [(3)H]glutamate release in rat brain slices and block convulsions in the maximal electroshock test in mice. We found that the hydroxyl function in the 4'-position is crucial for improving the sodium channel blocking properties. Moreover, the stereochemistry and the topology of the N-linked side chain also influence this interaction. Indeed, the affinity is improved by an aromatic substitution in the side chain. By modifying the N substituent and the substitution pattern of the hydroxyl function, we were able to discover (2R)-[2alpha,3(S),6alpha]-1,2,3,4,5,6-hexahydro-6,11,11-tri-methyl-3-[2-(phenylmethoxy)propyl]-2,6-methano-3-benzazocin-10-ol hydrochloride. This compound was chosen as the best candidate for further pharmacological investigations.

A new benzomorphane derivative, [11C]methyl-BIII277CL, was evaluated as a potential radiotracer for visualizing the PCP-binding site of the N-methyl-D-aspartate (NMDA) receptor by positron emission tomography (PET). Methyl-BIII277CL was prepared by reacting the desmethyl compound (BIII277CL) with dimethylsulfate. The pharmacological profile of methyl-BIII277CL was determined by in vitro receptor-screening assays. At a concentration of 100 nM, methyl-BIII277CL showed a significant interaction with the PCP-binding site of the NMDA receptor (79% inhibition of specific binding) and the sigma-binding site (46% inhibition). In displacement assays using mice cortical membranes, methyl-BIII277CL displayed a high affinity at the PCP-binding site of the NMDA receptor (Ki = 49 +/- 14 nmol/L) and a 130-fold lower interaction with the sigma1-binding site (Ki = 6.35 +/- 0.26 micromol/L). For saturation experiments and in vivo studies, methyl-BIII277CL was radiolabeled with 11C at the O-position of the desmethyl precursor (BIII277CL) using [11C]methyliodide with a specific activity of 35-70 GBq/micromol at the end of synthesis (EOS). In saturation assays using rat whole brain membranes [11C]methyl-BIII277CL showed a Kd of 6 +/- 1 nmol/L and a Bmax of 670 +/- 154 fmol/mg protein. Biodistribution and PET studies in rats and pigs, however, indicated a lack of specific binding and unfavorable pharmacokinetics. Kinetic modeling using the 1-tissue compartment model demonstrated for [11C]methyl-BIII277CL a low distribution volume (Dv = 0.98 mL/mL(tissue)) and very high values for the kinetic parameters K1 and k2 (K1 = 0.36 mL/mL(tissue)/min and k2 = 0.37min(-1)) in pig cortex. [11C]methyl-BIII277CL, due to the lack of specificity in vivo, may not be a candidate for imaging the PCP-binding site of the NMDA receptor.

Two of the synthesized (-)-(1R,5R,9R)-N-homologues (N-but-3-enyl- and N-but-3-ynyl-5,9-dimethyl-2'-hydroxy-6,7-benzomorphan (9, 13)) were found to be about 20 times more potent than morphine in the mouse tail-flick assay (ED(50) = 0.05 mg/kg), and (-)-(1R,5R, 9R)-N-but-2-ynyl-5,9-dimethyl-2'-hydroxy-6,7-benzomorphan ((-)-(1R, 5R,9R)-N-but-2-ynylnormetazocine, 12) was about as potent as the opioid antagonist N-allylnormetazocine (AD(50) in the tail-flick vs morphine assay = 0.3 mg/kg). All of the homologues examined had higher affinity for the kappa-opioid receptor than the mu-receptor except (-)-N-but-2-ynyl-normetazocine (12), which had a kappa/mu ratio = 7.8 and a delta/mu ratio = 118. The (-)-N-2-cyanoethyl (3), -allyl (8), and -but-3-ynyl (13) analogues had good affinity (<10 nM) for delta-opioid receptors. Two homologues in the (+)-(1S,5S,9S)-normetazocine series, N-pent-4-enyl (24) and N-hex-5-enyl (25), were high-affinity and selective sigma(1)-ligands (K(i) = 2 nM, sigma(2)/sigma(1) = 1250, and 1 nM, sigma(2)/sigma(1) = 750, respectively); in contrast, N-allylnormetazocine (22) had relatively poor affinity at sigma(1), and its sigma(1)/sigma(2) ratio was <100.

This report concerns the synthesis and preliminary pharmacological evaluation of a novel series of kappa agonists related to the morphinan (-)-cyclorphan (3a) and the benzomorphan (-)-cyclazocine (2) as potential agents for the pharmacotherapy of cocaine abuse. Recent evidence suggests that agonists acting at kappa opioid receptors may modulate the activity of dopaminergic neurons and alter the neurochemical and behavioral effects of cocaine. We describe the synthesis and chemical characterization of a series of morphinans 3a-c, structural analogues of cyclorphan [(-)-3-hydroxy-N-cyclopropylmethylmorphinan S(+)-mandelate, 3a], the 10-ketomorphinans 4a,b, and the 8-ketobenzomorphan 1b. Binding experiments demonstrated that the cyclobutyl analogue 3b [(-)-3-hydroxy-N-cyclobutylmethylmorphinan S(+)-mandelate, 3b, MCL-101] of cyclorphan (3a) had a high affinity for mu, delta, and kappa opioid receptors in guinea pig brain membranes. Both 3a,b were approximately 2-fold more selective for the kappa receptor than for the mu receptor. However 3b (the cyclobutyl analogue) was 18-fold more selective for the kappa receptor in comparison to the delta receptor, while cyclorphan (3a) had only 4-fold greater affinity for the kappa receptor in comparison to the delta receptor. These findings were confirmed in the antinociceptive tests (tail-flick and acetic acid writhing) in mice, which demonstrated that cyclorphan (3a) produced antinociception that was mediated by the delta receptor while 3b did not produce agonist or antagonist effects at the delta receptor. Both 3a,b had comparable kappa agonist properties. 3a,b had opposing effects at the mu receptor: 3b was a mu agonist whereas 3a was a mu antagonist.

The key steps in the stereoselective synthesis of the tricyclic aminomethyl derivatives 19 and 20 and the aminoethyl substituted 1,3-dioxanes 24 and 25 are nucleophilic addition of aryllithium intermediates to the nitroalkene 13, intramolecular transacetalization of the addition products 15 and 16 (only for the tricyclic derivatives 19 and 20) and subsequent reduction of the nitro group. The affinities of the secondary and tertiary amines 19c,d, 20c,d, 24c,d, and 25c,d for the ion channel binding site of the NMDA receptor, for mu-, kappa-, and sigma-receptors have been investigated. In the group of tricyclic compounds only 19d shows remarkable sigma-receptor affinity (Ki = 21.6/1.10 microM). In the 1,3-dioxane series the moderate mu- (Ki = 27.8 microM) and kappa-receptor affinity (Ki = 36 microM) as well as the high sigma-receptor affinity (Ki = 3.3 microM) of the (S,S,S)-configurated methylamine 24c should be emphasized. The pentan-1-ol 26, the side product isolated during the synthesis of 24c, is of particular interest because of its considerable affinity to mu- (Ki = 16.0 microM), kappa- (Ki = 2.8 microM), and sigma-receptors (Ki = 14.5/1.26 microM). The biphasic competition curves obtained during sigma-receptor binding studies of 19d and 26 (two Ki values) may be explained by different interaction with sigma-receptor subtypes.

A convenient enantioselective synthesis of (1R,5R,9R)- and (1S,5S, 9S)-9-alkyl-2-benzyl-6,7-benzomorphans (2a-c) which starts with naphthaldehyde is described. These compounds were designed to gain additional information on the structure-sigma binding relationship of the 6,7-benzomorphan class of sigma ligands. In contrast to pentazocine and most 6,7-benzomorphans, the (1R,5R,9R)-isomers of 2a-c showed greater affinity for the sigma(1) receptor than the (1S, 5S,9S)-isomers. Despite reversal of enantioselectivity at the sigma(1) sites, moderate affinity and enantioselectivity at the sigma(2) sites [greater affinity for (1R,5R,9R)-isomers than (1S,5S, 9S)-isomers] were maintained. A comparison of the binding affinities of 2a-c to the more conformationally flexible trans-2-alkyl-1-benzaminoethyl-1,2-dihydronaphthalenes (10a-c) suggested that the relatively rigid structure of 2a-c played an important part in their sigma(1) binding properties. These compounds, particularly (1R,5R,9R)-2-benzyl-9-methyl-6,7-benzomorphan [(-)-2a], which has a K(i) value of 0.96 nM, will be useful in further characterization of the sigma(1) receptor.

[formula: see text] Concise asymmetric syntheses of several benzomorphan derivatives have been accomplished using enantiopure 2,3-dihydro-4-pyridones as chiral building blocks.

A series of (+)-cis-N-normetazocine derivatives has been described, and their affinities for sigma1, sigma2, and phencyclidine (PCP) sites and opioid, muscarinic (M2), dopamine (D2), and serotonin (5-HT2) receptors were evaluated. The effect of the N-substitution with a substituted ethylamino spacer was investigated. Compounds 8c-11c displayed high affinities for sigma1 sites and for opioid receptors. Substitution of the second basic nitrogen either with alkyl or cycloalkyl substituents give compounds (1a-6a) with high affinity and selectivity for sigma1 binding sites. Compounds 1a-5a were further characterized in vivo, and their agonist/antagonist activity was evaluated. In mouse, compound 1a and 2a as well as haloperidol suppressed in a dose-related manner the stereotyped behavior induced by (+)-SKF 10,047. Compounds 3a-5a and (+)-pentazocine do not affect the stereotyped behavior induced by ip injection of (+)-SKF 10,047. Therefore, from this series of compounds we identified potent and selective sigma1 ligands which might prove useful to unveil the functional role of sigma1 sites.

We have synthesized a series of stereoisomeric 6,7-benzomorphan derivatives with modified N-substituents and determined their ability to antagonize the N-methyl-D-aspartate (NMDA) receptor-channel complex in vitro and in vivo. The ability of the compounds to displace [3H]-MK-801 from the channel site of the NMDA receptor in rat brain synaptosomal membranes and to inhibit NMDA-induced lethality in mice was compared with their ability to bind to the mu opioid receptor. Examination of structure-activity relationships showed that the absolute stereochemistry is critically important for differentiating these two effects. (-)-1R,9 beta,2"S-enantiomers exhibited a higher affinity for the NMDA receptor-channel complex than for the mu opioid receptor. The aromatic hydroxy function was also found to influence the specificity of the compounds. Shift of the hydroxy group from the 2'-position to the 3'-position significantly increased the affinity for the NMDA receptor-channel complex and considerably reduced the affinity for the mu opioid receptor. From this series of 6,7-benzomorphan derivatives, the compound 15cr.HCl [(2R)-[2 alpha, 3(R*),6 alpha]-1,2,3,4,5,6-hexahydro-3-(2-methoxypropyl)-6,11,11-trimethyl -2,6-methano-3-benzazocin-9-ol hydrochloride] was chosen as the optimum candidate for further pharmacological investigations.

The synthesis and sigma 1 and sigma 2 binding properties of several (+)- and (-)-2-benzyl- and 2-dimethylallyl-2'-substituted-5,9 alpha-dimethyl-6,7-benzomorphans (3 and 4) are presented. In agreement with previously reported binding data for 2-substituted 5,9 alpha-dimethyl-2'-hydroxy-6,7-benzomorphans (N-substituted-N-normetazocine), all (1S,5S,9S)-(+)-isomers showed higher affinity for the sigma 1 site than the corresponding (1R,5R,9R)-(-)-isomers. Replacement of the 2'-hydroxy group of (+)-2-benzyl-5,9 alpha-dimethyl-2'-hydroxy-6,7-benzomorphan [(+)-1f] with a 2'-NH2 and 2'-N(CH3)2 [(+)-3b and (+)-3c, respectively] had only a small effect on the sigma 1 Ki values. Changing the 2'-hydroxy group of (+)-1f to an H, F, Cl, Br, I, NHAc, or NHSO2CH3 resulted in a 5-fold or greater loss in potency. In contrast, replacement of the 2'-hydroxy group of (+)-2-(dimethylallyl)-5,9 alpha-dimethyl-2'-hydroxy-6,7-benzomorphan [(+)-1b, (+)-pentazocine] with a 2'-H or 2'-F group resulted in a 2-fold increase in potency. Conversion of (+)-1f to its 2'-desoxy analogue (+)-2d resulted in a 27.5-fold loss in affinity. This suggests that (+)-1f and other N-substituted benzomorphan analogues may be binding to single sigma 1 receptors in a different way or to different sigma 1 receptors. (-)-Pentazocine [(-)-1b] and its 2'-fluoro analogue, (-)-2-(dimethylallyl)-5,9 alpha-dimethyl-2'-fluoro-6,7-benzomorphan [(-)-4a] showed the highest potency for the sigma 2 binding site.

The synthesis of 2'-heptylcarbamoyloxy-2-methyl-6,7-benzomorphan is described. The compound is structurally related to the cholinesterase inhibitor heptylphysostigmine (MF 201) because the angular methyl group of the esoroline nucleus has been changed into a bridging carbon and the anilinic nitrogen has been replaced by a methylene group. This compound proved to be a potent cholinesterase in vitro inhibitor.

Addition of the beta-alanine derivative 6 to the homophthalaldehyde monoacetal 5 and subsequent LiAlH4-reduction led to the dihydroxy acetal 8, which was cyclized with acid to give the 5-aminomethyl-2,6-epoxy-3-benzoxocines 2a and 2b. The reaction of 5 with the anion of the beta-lactam 9 yielded two separable diastereomers: 10a with u,l-configuration and 10b with 1,1-configuration. Via the 2-benzopyran 11a (11b), the aminoalcohol 12a (12b), and the secondary amine 13a (13b), the beta-lactam adduct 10a (10b) was transformed to give the 5-(alpha-dimethylaminobenzyl)-2,6-epoxy-3-benzoxocine 3d (3b). The relative configurations of all these "beta-lactam route" products (10-13, 3d, and 3b) were established by their 1H-NMR-spectra. Attempts failed to get the missing diastereomers 3a and 3c by epimerization of the beta-lactams 11a and 11b or by reductive amination of the benzoyl derivatives 17a and 17b. Finally, 3a and 3c were obtained by phenylmagnesium bromide addition to the nitriles 21a and 21b, followed by LiAlH4-reduction, formaldehyde/NaBH3CN methylation and chromatographic separation. In the Irwin-screen (mouse) only 2a.HCl, 3b, and 3d (100 mg/kg body weight) caused weak central effects.

Under acidic conditions the secondary amines 10a and 10b, the primary amine 15, the amide 17a, and the urethane 17b were cyclized to yield the 2,6-epoxy-3-benzazocines 11a, 11b, 16, 18a and 18b, respectively. Ring closure of the inverse amide 5a, however, failed to give the tricyclic N/O-acetal 6. With LiAlH4 the epoxy bridge of the urethane 18b was opened to afford the bicyclic 3-benzazocine 20. While the N-(2-methoxyethyl) derivative 11b did not influence the behaviour of mice, the N-methyl derivative 11a showed strong central effects.

Unlabeled fluoro- and iodo-substituted ligands exhibiting very high affinity and selectivity for sigma receptors were synthesized based on three different structural classes of sigma receptor ligands. These compounds were evaluated for sigma receptor affinity and specificity in order to assess their potential as PET/SPECT imaging agents. Thus, (+)- and (-)-N-(5-fluoro-1-pentyl)normetazocines [(+)- and (-)-4] based on the (+)-benzomorphan class of sigma ligands were synthesized via N-alkylation of optically pure (+)- and (-)-normetazocine with 5-[(methylsulfonyl)oxy]-1-pentyl fluoride (11). (+)- and (-)-4 displaced [3H](+)-3-PPP with Ki values of 0.29 and 73.6 nM and [3H](+)-pentazocine with Ki values of 10.5 and 38.9 nM, respectively. The second class of PET/SPECT ligands was based upon the N-(arylethyl)-N-alkyl-2-(1-pyrrolidinyl)ethylamine class of sigma ligands; N-[2-(3,4-dichlorophenyl)-1-ethyl]-N-(3-fluoro-1-propyl)-2-(1- pyrrolidinyl)ethylamine (5) was obtained via N-alkylation of N-[2-(3,4-dichlorophenyl)-1-ethyl]-2-(1-pyrrolidinyl)ethylamine (14) with 3-fluoropropyl p-toluenesulfonate. 5 exhibited Ki values of 4.22 and 5.07 nM for displacement of [3H](+)-3-PPP and [3H](+)-pentazocine, respectively, comparable with the parent N-propyl compound. Attempts to synthesize N-[2-(3,4-dichlorophenyl)-1-ethyl]-N-[3- [(methylsulfonyl)oxy]-1-propyl]-2-(1-pyrrolidinyl)ethylamine (26), a precursor to 5 that could conceivably be converted to [18F]-5 by treatment with 18F-, proved unsuccessful. The sequence of regioselective nitration, catalytic hydrogenation, and diazotization followed by NaI quench of N-[2-(3,4-dichlorophenyl)-1-ethyl]-N-methyl-2-(1- pyrrolidinyl)ethylamine (2) afforded the iodinated ethylenediamine N-[2-(2-iodo-4,5-dichlorophenyl)-1-ethyl]-N-methyl-2-(1- pyrrolidinyl)ethylamine (8), a potential SPECT ligand for sigma receptors. This compound showed an affinity of 0.54 nM ([3H](+)-3-PPP) comparable with the parent compound 2 (Ki = 0.34 nM, [3H](+)-3-PPP). Ligand 8 exhibited a similar potency against [3H](+)-pentazocine. The third class of high-affinity sigma receptor ligands was rationalized based on rearrangement of the bonds in ethylenediamine 2 to give 1-[2-(3,4-dichlorophenyl)-1-ethyl]-4-(1-propyl)piperazine (3). This compound exhibited very high affinity (Ki = 0.31 nM, [3H](+)-3-PPP) and selectivity for sigma receptors.(ABSTRACT TRUNCATED AT 400 WORDS)

Benzomorphans with an electrophilic group in the nitrogen substituent were prepared as potentially irreversible ligands for the kappa-opioid receptor. These were synthesized from products of the reaction of normetazocine with the enantiomers of 5-(iodomethyl)-gamma-butyrolactone (11). alpha-Methylene gamma-lactones 5 and 7 and endocyclic alpha,beta-unsaturated gamma-lactones 8 and 9 were prepared from the corresponding saturated gamma-lactones 13 and 23 possessing the "active" (1R,5R,9R)-benzomorphan stereochemistry. Only gamma-lactones 8, 9, 13, and 23, lacking the exocyclic methylene group, retain significant affinities for opioid receptor binding sites when compared with the reference compounds (2"S)-3 and (2"R)-3. As observed with these references compounds, greater binding affinity is also seen with gamma-lactone diastereomers having the 2"S stereochemistry in the nitrogen substituent. Although the gamma-lactones do not bind irreversibly in opioid receptor preparations, they do show kappa-receptor selectivities comparable to those observed for the reference compounds.

2,9alpha-Dimethyl-2'-hydroxy-6,7-benzomorphan (14) has been synthesized in six to seven steps from trans-3,4-dihydro-4-(2-dimethylaminoethyl)-6-methoxy-3-methyl-1(2H)-naphthalenone (1). The key reaction of the sequence was mercuric acetate cyclization of trans-1,2-dihydro-1-(2-methylaminoethyl)-7-methoxy-2-methylnaphthalene (8) which gave a mixture of 9alpha-methyl-8alpha-hydroxy-6,7-benzomorphan (9, 49%), the corresponding acetate (10, 13%), and the 9beta-methyl-8alpha-hydroxy-6,7-benzomorphan (11, 5%). In the presence of Et3N, the yields were 16, 37, and 0%, respectively. Structural assignments are based on ir, NMR, and mass spectral data and on chemical conversions.

A new non-narcotic analgesic, 2-[3-(p-fluorobenzoyl)-n-propy]-5alpha,9alpha-dimethyl-2'-hydroxy-6,7-benzomorphan (ID-1229) has been prepared from 5alpha,9alpha-dimethyl-2'-hydroxy-6,7-benzomorphan. The analgesic activities of ID-1229 were several times more potent than those of pentazocine in the acetic acid writhing test in mice, bradykinin test in rats, Randall-Selitto's test in rats, and the electrical stimulation test in mice, while, ID-1229 showed little activity in both the tail pinch test and the hot plate test. ID-1229 did not show anti-narcotic activity in the morphine-combined test, and the Straub tail phenomenon was not observed in ID-1229. ID-1229 showed CNS activities in some tranquilizing tests, but did not show activity in several other CNS tests. The CNS potency is condiserably weaker as compared with haloperidol or diazepam, and the pattern of CNS activities in ID-1229 is quite different from those of both compounds. ID-1229 is a potent non-narcotic analgesic with tranquilizing activity, which is quite free from the undersirable side effects of morphine or morphine-like compounds including pentazocine.

The N-arginyl derivative of methionine-enkephalin (fragment 60-65 of beta-lipotropin) has been shown to be equiactive with the parent pentapeptide, despite the fact that the tyrosine amino group in this compound has been neutralized by the formation of an amide linkage. A series of N-(amino acid) derivatives of (-)-5,9 alpha-diethyl-2'-hydroxybenzomorphan was prepared and evaluated for analgesic activity. In vitro activities were found to vary greatly, depending on the nature of the amino acid used. The N-arginyl derivative was found to be equipotent to (-)-5,9 alpha-diethyl-2'hydroxybenzomorphan and also to methionine-enkephaline in the naloxone binding assay.

2,9beta-Dimethyl-2'-hydroxy-6,7-benzomorphan (18) has been synthesized from m-methoxyphenylacetone (6a) or m-methoxyphenylacetonitrile (1) via bromo-alpha-tetralone (10). Isomeric bromo-alpha-tetralone 9, instead of undergoing cyclization to a 6,7-benzomorphan, gave aromatization product 12. The structures and stereochemical assignments of 9, 10 (and thus 7 and 8), and 18 follow from analogy and from NMR data of 9, 10, 17, and 18. Compound 18 and the deoxy analog 16 are as potent as morphine and codeine, respectively, as analgetics (mice) and are without physical dependence capacity (monkeys).

A series of N-substituted 9alpha-ethyl-2'-hydroxy-5-methyl-6,7-benzomorphans was synthesized and evaluated for their narcotic analgesic and antagonistic activities. Compounds 2a and 22 were as potent as morphine in the writhing (PPQ) and hot-plate tests, while a number of compounds demonstrated antagonistic activities greater than nalorphine. Generally, the compounds in this series show activities somewhat greater than the comparable compounds in the 5,9alpha-dimethyl-6,7-benzomorphan series for analgesic effect and similar or slightly less antagonistic potency.

A fluorinated derivative of the benzomorphan opiate agonist phenazocine, (+/-)-5,9 alpha-dimethyl-2-[2-(4-fluorophenyl)ethyl]-2'-hydroxy-6, 7-benzomorphan (fluorophen), was prepared by N-acylation of (+/-)-5,9 alpha-dimethyl-2'-hydroxybenzomorphan with (p-fluorophenyl)acetyl chloride, followed by diborane reduction of the resulting amide. Fluorination produces only a twofold opiate receptor affinity loss when measured either by bioassay or receptor binding (selectivity mu congruent to delta greater than kappa). Labeled with 18F, fluorophen should be sufficiently potent to be useful as an in vivo probe for visualizing opiate receptors by positron emission transaxial tomography (PETT).

The reaction of N-2,4,5-tribenzyloxyphenyl)ethyl methanesulfonate, prepared in a seven-step sequence, with normetazocine followed by hydrogenolysis of the benzyloxy-protecting groups, gave N-(2,4,5-trihydroxyphenethyl)normetazocine. This compound was prepared to study the effect of a narcotic analgesic containing a functional group which could be activated in situ to a moiety potentially capable of reacting irreversibly with the narcotic receptor. This 6-hydroxydopamin derivative of normetazocine did not prove to be a useful affinity label. Its low toxicity could indicate the necessity for the formation of an aminochrome system for the expression of toxicity by 6-hydroxydopamine.

Acryloyl, methacryloyl, N-vinylcarbamoyl, and methacryloyl-glycyl derivatives of the morphine antagonist (--)-alpha-5,9-dimethyl-2-(3-furylmethyl)-2'-hydroxy-6,7-benzomorphane have been synthesized. The different unsaturated derivatives were copolymerized with appropriate comonomers to yield water-soluble polymers. Pharmacological tests in mice showed a 2--30 fold increase in duration of action in comparison to the free antagonist. The binding of the antagonist to the polymers resulted in a reduced acute toxicity.

The eight optically active stereoisomers and the corresponding four racemic forms of 5,9-dimethyl-2'-hydroxy-2-tetrahydrofurfuryl-6,7-benzomorphan (1) have been prepared. Depending on their configurations these compounds are potent analgesics or inactive substances in mice. The analgesics attain potencies up to about a hundred times that of morphine but they do not show morphine-like side effects in mice nor do they suppress abstinence in withdrawn morphine dependent monkeys. Their therapeutic ratios are favorable and, in the case of la-1 and la-2, exceptionally good. Configuration-activity relationships are discussed. R configuration of the N-tetrahydrofurfuryl group is a major prerequisite for high analgesic potency.

2,5-Dimethyl-2'-hydroxy-9 alpha-(3-methylbutyl)-6,7-benzomorphan, the 9 beta-analogue, and 9 alpha-N-substituted (N-ethyl, propyl, butyl, pentyl, hexyl, phenylethyl, allyl, and cyclopropylmethyl) compounds were synthesized and evaluated biochemically and pharmacologically. The 9 beta N-methyl compound was found to be as potent as morphine in the mouse hot plate assay and had one-seventh the affinity of morphine for the opioid receptor. The N-alkyl and N-phenethyl 9 alpha-substituted compounds were either inactive or relatively ineffective as antinociceptive agents. None of the examined compounds substituted for morphine in single-dose suppression studies in the rhesus monkey. The N-cyclopropylmethyl compound in the 9 alpha series had half the narcotic antagonist potency of nalorphine and one-eighth of its affinity for the opioid receptor. The 9 alpha-(3-methylbutyl) moiety, unlike bulky substituents in the 9 beta position of 6,7-benzomorphans, generally lowers affinity for the mu opioid receptor and diminishes their in vivo activity as agonists or antagonists.

The benzomorphan analogues, 8-hydroxy-3-methyl-2,3,4,5-tetrahydro-1,4-methano-1H-3-benzazepine (1), 8-hydroxy-2-methyl-2,3,4,5-tetrahydro-1,4-methano-1H-2-benzazepine (2), 9-hydroxy-2-methyl-1,2,3,4,5,6-hexahydro-1,5,-methano-2-benzazocine (3), and 10-hydroxy-2-methyl-2,3,4,5,6,7-hexahydro-1,6-methano-1H-2-benzazonine (4), have been synthesized in order to evaluate their analgetic activity. Only slight analgetic activity was found in any of these compounds. The importance of nitrogen to aromatic ring distance for the analgetic-receptor interaction is discussed.

C16H22NO+2.Cl-, Mr = 295.808, monoclinic, P2(1), a = 11.967 (1), b = 12.529 (1), c = 9.9369 (9) A, beta = 93.00 (1) degrees, V = 1487.8 (2) A3, Z = 4, Dm = 1.32 (2), Dx = 1.321 Mg m-3, lambda(Cu K alpha) = 1.54178 A, mu(Cu K alpha) = 2.289 mm-1, F(000) = 632, T = 291 K, final R = 0.040 for 2448 observed reflections. The two molecules present in the asymmetric unit are linked by an extensive network of hydrogen bonds, including several of the less common (C-)H...O and (C-)-H...Cl types. This interpretation is substantiated by a Mulliken population analysis resulting from CNDO/2 calculations. The major effect of the presence of the epoxyethano bridge is a marked flattening about the N atom of the piperidinium ring. Whether this is sufficient to explain the inactivity of the compound at the opioid kappa receptor is not clear.

The N-(2-cyanoethyl)-9alpha-ethyl-5-methyl-6,7-benzomorphan (1c) is a more potent antinociceptive and has stronger receptor binding affinity than its N-methyl analogue 1b. The N-(2-cyanoethyl)-4-phenylpiperidine compounds 2b and 3b were almost inactive compared to their N-methyl congeners 2a and 3a, respectively. It appears that the pharmacological effect of the N-(2-cyanoethyl) moiety is dependent on the opioid on which it is substituted.

The levo and dextro isomers of 2,5-dimethyl-2'-hydroxy-9alpha- and -9beta-propyl-6,7-benzomorphans have been prepared. The analgesic potency and physical dependence capacity of the optical isomers and their racemic parents were determined. The 9alpha-propyl levo isomer was analgesically equipotent with morphine; the 9beta-propyl levo isomer was considerably more potent subcutaneously and equipotent orally. None of the optical isomers suppressed the withdrawal syndrome; the 9beta-propyl levo isomer exacerbated the withdrawal syndrome.

The 2,5-dimethyl-2'-hydroxy-9alpha- and-beta-propyl-6,7-benzomorphans were synthesized from 4-methyl-3-propylpyridine in five steps, in an overall yield of 14 and 5%, respectively. The required 4-methyl-3-propylpyridine was prepared in an overally yield of 34% by a four-step sequence. The benzomorphans were about as potent as, or more potent than, morphine in vivo.

In a benzomorphan bearing an antagonist side chain, introduction on the methano bridge of a hydroxyl oriented away from nitrogen has little effect on antagonist activity whereas a hydroxyl oriented toward nitrogen enhances this activity. Hydroxylation tends to decrease analgesic activity.