Stereoisomers of N-allylnormetazocine: phencyclidine-like behavioral effects in squirrel monkeys and rats.

(+/-)-N-Allylnormetazocine is a benzomorphan opioid with psychotomimetic effects. The pure stereoisomers of this compound, as well as the racemic mixture, were compared to phencyclidine for their behavioral effects on squirrel monkeys and rats trained to discriminate phencyclidine from saline. Dose-response determinations were made for responses to phencyclidine, to a racemic mixture of N-allylnormetazocine, and to the pure levo and dextro isomers of N-allylnormetazocine. In both rats and monkeys, the dextro isomer and the racemic mixture produced dose-dependent responses appropriate for phencyclidine; the levo isomer did not produce the responses appropriate for phencyclidine at any of the doses tested. In both species, the levo isomer was more potent than the dextro isomer in decreasing the rate of responding. Thus racemic N-allylnormetazocine is a mixture of compounds that produce different behavioral effects.

Analgesic properties of the tetrahydrocannabinols, their metabolites, and analogs.

The tetrahydrocannabinols from marihuana were found to have moderate analgesic activity in mice by the hot-plate test (sc administration). Of the several metabolites of these two compounds tested, only the 11-hydroxy derivatives were more potent than the parent compounds. Analogs 1 and 2 (9-demethyl relatives which cannot be metabolized to 11-hydroxy compounds), both of which produce a pharmacological profile generally similar to that of delta8- and delta9-THC, were analgesically inert. This suggests that metabolism to 11-hydroxy congeners may be necessary for the mediation of analgesic activity in the mouse hot-plate test but not for other pharmacologic effects produced by these substances which we have examined.

Synthesis and pharmacology of 2,9alpha-dimethyl-2'-hydroxy-6,7-benzomorphan.

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.

9-Nor-9-hydroxyhexahydrocannabinols. Synthesis, Some behavioral and analgesic properties, and comparison with the tetrahydrocannabinols.

The racemic mixture and levo isomer of both 9-nor-9alpha-hydroxyhexahydrocannabinol and its 9beta-hydroxy isomer were prepared. Both alpha-and beta-hydroxy compounds were active in the dog ataxia test and depressed spontaneous activity in mice. However, only the beta-hydroxy compound was an analgesic in mice morphine-like potency. The behavioral and analgesic properties of these compounds may be mediated through different sites or mechanisms and may, therefore, be separable.

Synthesis and pharmacology of 5-noralkyl-9beta-methyl-6,7-benzomorphans and stereochemistry of some intermediates.

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).

Synthesis and analgesic activities of 2,5-dimethyl-2'-hydroxy-9alpha- and -beta-propyl-6,7-benzomorphans.

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.

Some 9-hydroxycannabinoid-like compounds. Synthesis and evaluation of analgesic and behavioral properties.

A series of 9-hydroxylated cannabinoid-like compounds was prepared and tested for analgesic properties in mice and behavioral properties in dogs. Although the prototype compound, 9-nor-9-hydroxyhexahydrocannabinol, has potent antinociceptive activity in laboratory animals, the new analogues were relatively inactive. All of the compounds produced an alteration of behavior in unanesthetized dogs. Two of the compounds produced cannabinoid-like effects and the other two produced general CNS depression.

Synthesis and pharmacological activity of some N-alkyl-substituted 9alpha-ethyl-2'-hydroxy-5-methyl-6,7-benzomorphans.

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.

Synthesis, optical resolution, absolute configuration, and preliminary pharmacology of (+)- and (-)-cis-2,3,3a,4,5,9b-hexahydro-1-methyl-1H- pyrrolo-[3,2-h]isoquinoline, a structural analog of nicotine.

Title compound, 8, has been synthesized from isoquinolinone, 1 (an improved preparation for which is presented) and separated into its antipodes with D- and L-di-p-toluoyltartaric acids. These antipodes and the racemic precursor have been evaluated (and found active) in two in vivo systems for their effects. The most potent of the three, (+)-8, has an ED50 of 7.13 mumol/kg for inhibition of spontaneous activity and 7.45 mumol/kg for antinociception compared to 4.44 and 4.81 mumol/kg, respectively, for (S)-(-)-nicotine. Compounds (-)-8 and 7 are about one-fourth as potent. Isomer (+)-8 has the 3aR,9bS configuration, the latter corresponding to (S)-(-)-nicotine as determined by X-ray crystallography. However, (+)-8 failed to compete for [3H]-nicotine binding, and its pharmacological effects were not blocked by mecamylamine. These bridged nicotine analogs either are binding to an as-yet-unidentified nicotinic receptor or they represent a novel class of non-nicotinic analgesics.

Synthesis of 2-exo- and 2-endo-mecamylamine analogues. Structure-activity relationships for nicotinic antagonism in the central nervous system.

Nine analogues of mecamylamine (2) which differ in the number and substitution pattern of methyl groups, were prepared. In four of these analogues the amine functionality is in an endo orientation. Enantiomers of 2-endo- and 2-exo-N-methylfenchylamine (25 and 26, respectively) were also prepared. The hydrochloride salts of these compounds were tested for nicotinic antagonism relative to mecamylamine in vivo and none was found to be as potent as mecamylamine, although a broad range of activity was observed. In general, methyl substituents at the C1, C2, and C7 positions of the mecamylamine structure do not appear to be significant for antagonistic activity. Methyl substituents at C3, however, appear to be very important for activity. Three sets of enantiomers of N-methylfenchylamine analogues, 28-30, possessing structural features of mecamylamine and nicotine were also prepared. These compounds were inactive as antagonists. Only a small degree of stereoselectivity was elicited in this series, less than that seen with enantiomers of nicotine. Antagonists with the exo N-methylamine functionality are slightly more active than the endo isomers. The extent to which structural modification might change lipophilicities was estimated through calculated partition coefficients; such changes alone appeared insufficient to explain differences in activities of the analogues. Lastly, a tolerance for a tertiary (dimethyl) amine functionality was demonstrated in addition to the lack of tolerance for bulkier substituents at C3 or on the nitrogen.

Analgetic activity and in vitro binding constants of some N-alkyl-3-benzazocines.

A homologous series of 3-alkyl-1,2,3,4,5,6-hexahydro-8-hydroxy-6-methyl-3-benzazocines (2) has been synthesized. Analgetic activity and binding constants for the opiate receptor for 2 and for an analogous series of benzomorphans (1 and 3) are reported. In 1, hot-plate analgesic activity is lost on increase of the N-alkyl chain length from ethyl through butyl (lc-e) and regained with amyl (lf) and hexyl (lg). Compounds lc-e show that antagonist properties and binding constants are similar throughout the series. With 2, where there has been loss of steric constraints through removal of the 2,6-methano bridge of 1 and 3, greatly diminished analgetic activity and receptor affinity and no antagonist properties were observed. Like 1, however, greatest agonist activity was shown by the N-methyl (2c), amyl (2g), hexyl (2h), and heptyl (2i) homologs and there is a parallel of in vitro binding strength and analgetic activity.

Racemic and optically active 2,9-dimethyl-5-(m-hydroxyphenyl)morphans and pharmacological comparison with the 9-demethyl homologues.

2,9 alpha-Dimethyl-5-(m-hydroxyphenyl)morphan (3a) has been synthesized from 5-(m-methoxyphenyl)-2-methyl-9-oxomorphan (4) and resolved into its enantiomers (+)-3a and (-)-3a. The assigned alpha-orientation of the 9-methyl group was derived from studies of induced NMR shifts using Eu(fod)3-d27. Compound (+)-3a has inappreciable agonist (antinociceptive) activity in mice, and (-)-3a shows codeine-like potency in the hot-plate and writhing tests only. The 9-demethyl homologues, (+)-1 and (-)-1, are strong agonists, about as potent as morphine in these tests as well as in the tail-flick assay. The racemic compound 3a and (+)-3a, but not (-)-3a, exhibit low-potency, narcotic-antagonist activity in mice (tail-flick test, vs. morphine). All three, however, precipitate abstinence in nonwithdrawn, morphine-dependent rhesus monkeys. Monkey studies with the 9-demethyl homologues confirmed earlier results showing that (+)-1, suppressing abstinence in withdrawn animals, has high physical dependence capacity, while (-)-1 has none. Instead, (-)-1 precipitates abstinence in nonwithdrawn animals. Studies in rats and isolated organs (guinea pig ileum and mouse vas deferens) and receptor-binding assays confirm the quite different opioid-action profiles of (+)-1 and (-)-1, which thus might interact with different opioid receptors. Catalytic hydrogenation of the methiodide (7) of 5 gave, instead of the expected epimer of 3a, ring-opened compound 8.

Antipodal alpha-N-(methyl through decyl)-N-normetazocines (5,9 alpha-dimethyl-2'-hydroxy-6,7-benzomorphans): in vitro and in vivo properties.

The enantiomeric (-)- and (+)-N-(methyl through decyl) normetazocines (5,9 alpha-dimethyl-2'-hydroxy-6,7-benzomorphans) were synthesized and their in vitro and in vivo activities determined. Increasingly bulky enantiomeric N-alkyl homologs were prepared until their interaction with the sigma 1 receptor decreased and their insolubility became a hindrance to their evaluation in vivo and/or in vitro. The (-)-methyl, -pentyl, -hexyl, and -heptyl homologs were essentially as potent as, or more potent than, morphine in the tail-flick, phenylquinone, and hot-plate assays for antinociceptive activity; the (-)-propyl homolog had narcotic antagonist activity between that of nalorphine and naloxone in the tail-flick vs morphine assay, and it also displayed antagonist properties in the single-dose suppression assay in the rhesus monkey. The antinociceptively potent (-)-heptyl homolog did not substitute for morphine in monkeys but did show morphine-like properties in a primary physical-dependence study in continuously infused rats. All five potent compounds showed high affinity for the mu opioid receptor from both rat and monkey preparations and the kappa opioid receptor (< 0.05 microM), and all except the (-)-methyl homolog interacted reasonably well at the delta receptor (K(i) < 0.1 microM). The (-)-propyl compound was equipotent (K(i) 1.5-2.0 nM) at mu and kappa receptors. The pattern of interaction of the (-)-enantiomeric homologs with mu receptors from rat and monkey preparations was similar, but not identical. The enantioselectivity of the homologs for mu receptors was greater in the rat than in the monkey preparation for all but the N-H and butyl compounds, and the enantioselectivity of the lower homologs (methyl through butyl) for the mu (monkey) receptor was greater than for the kappa or delta receptors. However, bulkier homologs (hexyl through decyl) displayed higher enantioselectivity at kappa or delta receptors than at the mu (monkey) receptor. The (+)-butyl through (+)-octyl homologs were essentially equipotent with, or more potent than, (+)-pentazocine at the sigma receptor. Only the (+)-H and (+)-methyl homologs had high affinity (< 0.05 microM) at PCP binding sites.

Common stereospecificity of opioid and dopamine systems for N-butyrophenone prodine-like compounds.

The two optical isomers of 1-[3-(p-fluorobenzoyl) propyl]-3-methyl-4-phenyl-4-propionoxypiperidine (FPP) were obtained by resolution of (+/-)-r-3-methyl-4-phenyl-c-4-piperidinol followed by N-alkylation and O-propionylation. These, as well as the racemate, were evaluated for their antinociceptive, opioid, and neuroleptic properties using in vivo and in vitro test systems. The results are remarkable in two respects, namely, the dextrorotatory isomer is consistently the most potent on all tests, and it acts on both opioid (mu) and neuroleptic (D2) receptors.

Enantiomeric N-substituted N-normetazocines: a comparative study of affinities at sigma, PCP, and mu opioid receptors.

The optical antipodes of N-allyl-N-normetazocine (2; SKF 10047, NANM) were the original compounds used for the classification of the sigma receptor as distinct from other receptors such as the PCP (NMDA), opioid, and dopamine receptors. Later studies showed that (+)-N-(dimethylallyl)-N-normetazocine [(+)-4, (+)-pentazocine] was more potent and selective for the sigma receptor. In order to gain additional structure-activity relationship information, several N-substituted N-normetazocine analogs were prepared and evaluated for their sigma-1 ([3H]-(+)-3-PPP or [3H]-(+)-pentazocine), PCP ([3H]TCP), and mu opioid ([3H]DAMGO) receptor binding affinities. (+)-N-Benzyl-N-normetazocine [(+)-10)] possessed subnanomolar affinities for the sigma site, Ki = 0.67. The analog (+)-10 showed greater than 14,000- and 2400-fold selectivity, respectively, for the sigma receptor relative to the PCP and mu opioid receptors. The N-substituted N-normetazocines were enantioselective for the sigma site. The (+)-N-benzyl analog, (+)-10, showed a 55-fold selectivity relative to (-)-10. Analysis of the data also revealed that (+)-normetazocine [(+)-1] [Ki = 30 nM] possessed the highest affinity for the PCP receptor. However, (+)-metazocine [(+)-5] (Ki = 41 nM) was the most selective compound for the PCP receptor relative to the sigma (51-fold) and mu opioid (greater than 200-fold) sites.

Synthesis and in vitro and in vivo activity of (-)-(1R,5R,9R)- and (+)-(1S,5S,9S)-N-alkenyl-, -N-alkynyl-, and -N-cyanoalkyl-5, 9-dimethyl-2'-hydroxy-6,7-benzomorphan homologues.

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.

Hexahydro-1H-1-pyrindines from acid rearrangement of 9-alkylidene-5-(m-methoxyphenyl)-2-methylmorphans. A new structural type of narcotic antagonists.

9-Methylene- and 9-ethylidene-5-(m-methoxyphenyl)-2-methylmorphans (1, 2) and refluxing 48% HBr have given rearrangement products 3 and 4, respectively. The structure of 4 [4a-ethyl-2,4a,5,6,7,7a-hexahydro-4-(3-hydroxyphenyl)-1-methyl-1H-1- pyrindine] was determined by X-ray crystallography and that of 3 [1,4a-dimethyl-2,4a,5,6,7,7a-hexahydro-4-(3-hydroxyphenyl)-1-methyl-1H- pyrindine] follows from analogy and NMR data. Compounds 3 and 4 are opioid antagonists of about the potency of nalorphine in the tail-flick vs. morphine assay and precipitate a complete abstinence syndrome in morphine-dependent monkeys. Both are nearly devoid of antinociceptive activity and they have about 0.025 times the affinity of nalorphine for the mu opioid receptor.

Probes for narcotic receptor mediated phenomena. 13. Potential irreversible narcotic antagonist-based ligands derived from 6,14-endo-ethenotetrahydronororipavine with 7-(methoxyfumaroyl)amino, (bromoacetyl)amino, or isothiocyanate electrophiles: chemistry, biochemistry, and pharmacology.

N-Allyl-, N-(cyclopropylmethyl)-, and N-propyl-endo-ethenotetrahydronororipavines (N-substituted 6,14-endo-etheno-4,5-epoxy-3-hydroxy-6-methoxymorphinans) were synthesized with potential acylating or alkylating moieties at the C-7 position (isothiocyanato, (bromoacetyl)amino, and (methoxyfumaroyl)amino) and examined in vivo for their narcotic agonist and antagonist activities and for their ability to interact with opioid receptors in vitro. The N-(cyclopropylmethyl)-substituted compounds were found to have the highest affinity for opioid receptors among these N-substituted compounds, although all of them were found to be reasonably potent narcotic antagonists in the mouse tail flick vs. morphine assay. Their in vivo potency ranged from 1/8 to 4 times that of nalorphine on intravenous injection in mice. Rat brain membrane binding studies indicated that the compounds interacted with opioid receptors with potencies that ranged from 0.5 times that of morphine (8c, 9c, and 10c) to 0.017 that of morphine (8b). Among the compounds studied here, only the previously reported isothiocyanato compound (10c) and (methoxyfumaroyl)amino compound (8c) interacted irreversibly and selectively with mu or delta opioid receptors, respectively, in assays using NG108-15 neuroblastoma-glioma hybrid cells and/or in a rat brain membrane preparation. Both 8c and 10c were found to interact irreversibly, to a limited extent, with kappa opioid sites in rat brain membranes in which the mu and delta opioid receptors were depleted by interaction with the mu-selective irreversible ligand BIT and the delta-selective irreversible ligand FIT. Neither compound showed irreversible actions in the electrically stimulated mouse vas deferens preparation.

Optically pure (+)-nicotine from (+/-)-nicotine and biological comparisons with (-)-nicotine.

Optically pure (+)-nicotine has been obtained from (+/-)-nicotine using a combination of d-tartaric acid and di-p-toluoyl-l-tartaric acid. As the di-d-tartrate salt, (+)-nicotine is less potent than (-)-nicotine di-l-tartrate in producing lethality in mice, on blood pressure in anesthetized rats, and in the isolated guinea-pig ileum, indicating substantial stereospecificity for nicotine receptors. Potency ratios are 0.14, 0.06, and 0.019, respectively.

Synthesis, absolute configuration, and molecular modeling study of etoxadrol, a potent phencyclidine-like agonist.

Etoxadrol (2a), one of the eight possible optical isomers of 2-ethyl-2-phenyl-4-(2-piperidyl)-1,3-dioxolane, was synthesized from (S,S)-1-(2-piperidyl)-1,2-ethanediol, which was obtained from cleavage of dexoxadrol (1a, (S,S)-2,2-diphenyl-4-(2-piperidyl)-1,3-dioxolane). The absolute configuration of etoxadrol hydrochloride, a phencyclidine-like compound biologically, was determined to be 2S, 4S, and 6S at its three chiral centers by single-crystal X-ray analysis. Epietoxadrol (2b), epimeric with etoxadrol at the C-2 center, was also obtained from the synthesis. This much less potent enantiomer has the 2R,4S,6S configuration. The affinity of etoxadrol to the phencyclidine binding site was found to be comparable to that of phencyclidine itself and was 35 times more potent than its epimer, epietoxadrol. Three diastereomeric mixtures were prepared that had low affinity for the phencyclidine site. In studies of the discriminative stimulus properties of these compounds, it was found that only etoxadrol substituted for the phencyclidine stimulus. With use of computer-assisted molecular modeling techniques, a hypothetical phencyclidine binding site model has been developed that, unlike our former hypothesis based on Dreiding models, correctly predicts the higher affinity of etoxadrol and the lesser affinity of epietoxadrol for the phencyclidine site.