Using Redox-Active Ligands to Generate Actinide Ligand Radical Species.

Using a redox-active dioxophenoxazine ligand, DOPO (DOPO = 2,4,6,8-tetra-tert-butyl-1-oxo-1H-phenoxazine-9-olate), a family of actinide (U, Th, Np, and Pu) and Hf tris(ligand) coordination compounds was synthesized. The full characterization of these species using 1H NMR spectroscopy, electronic absorption spectroscopy, SQUID magnetometry, and X-ray crystallography showed that these compounds are analogous and exist in the form M(DOPOq)2(DOPOsq), where two ligands are of the oxidized quinone form (DOPOq) and the third is of the reduced semiquinone (DOPOsq) form. The electronic structures of these complexes were further investigated using CASSCF calculations, which revealed electronic structures consistent with metals in the +4 formal oxidation state and one unpaired electron localized on one ligand in each complex. Furthermore, f orbitals of the early actinides show a sizable bonding overlap with the ligand 2p orbitals. Notably, this is the first example of a plutonium-ligand radical species and a rare example of magnetic data being recorded for a homogeneous plutonium coordination complex.

Electronic and magnetic properties of EuNi2-δ Sb2 structural variants.

X-ray diffraction, magnetic susceptibility, magnetization, heat capacity and electrical resistivity results are reported for single crystals of two structural variants of EuNi2-δ Sb2 that crystallize in the CaBe2Ge2 and ThCr2Si2-type structures. While the former occurs with a stoichiometric ratio, the latter exhibits a Ni site vacancy (δ = 0.36). Both systems exhibit similar magnetic behavior at elevated temperatures, where there is an isotropic Curie-Weiss temperature dependence that indicates an antiferromagnetic exchange interaction between divalent europium ions, although it is stronger for the CaBe2Ge2-variant. At low temperatures, the differing structural environments that surround the Eu ions result in distinct ordering behavior. The CaBe2Ge2-variant orders antiferromagnetically near T N1 = 6.9 K and then undergoes a first order phase transition at T M = 4.6 K. The ThCr2Si2-variant exhibits simpler behavior, with antiferromagnetic ordering at T N2 = 5.6 K. For both compounds, an applied magnetic field suppresses the ordering temperatures and induce metamagnetic phase transitions, while applied pressure causes the ordering temperatures to increase. From these results, EuNi2-δ Sb2 emerges as a useful system in which to study the impact of structural variation on magnetism in a Eu-based metal.

Superconductivity in a uranium containing high entropy alloy.

High entropy alloys (HEA) are an unusual class of materials where mixtures of elements are stochastically arrayed on a simple crystalline lattice. These systems exhibit remarkable functionality, often along several distinct axes: e.g., the examples [TaNb]1-x(TiZrHf)x are high strength and damage resistant refractory metals that also exhibit superconductivity with large upper critical fields. Here we report the discovery of an f-electron containing HEA, [TaNb]0.31(TiUHf)0.69, which is the first to include an actinide ion. Similar to the Zr-analogue, this material crystallizes in a body-centered cubic lattice with the lattice constant a = 3.41(1) Å and exhibits phonon mediated superconductivity with a transition temperatures Tc ≈ 3.2 K and upper critical fields Hc2 ≈ 6.4 T. These results expand this class of materials to include actinide elements, shows that superconductivity is robust in this sub-group, and opens the path towards leveraging HEAs as functional waste forms for a variety of radioisotopes.

A novel cage for actinides: A 6W4Al43 (A = U and Pu).

We report on synthesis and characterization of the compounds A 6W4Al43 (A = U and Pu), that form in the hexagonal Ho6Mo4Al43 caged-structure family. The A ions reside within W/Al cages where the A-A nearest neighbors form dimers between adjacent W/Al cages, with U-U and Pu-Pu distances of 3.3892 [Formula: see text] and 3.4080 [Formula: see text], respectively. While the W/Al networks provide environments similar to those of other cage-like materials (e.g. filled skutterudites), the atomic displacement parameters from single crystal x-ray diffraction measurements show that the A-ions do not exhibit rattling behavior. We find that there is site interchange disorder on one of the W/Al sites. Magnetic susceptibility measurements show that U6W4Al43 displays anisotropic Curie-Weiss behavior where it fits to the data yield an effective magnetic moment near 2.0 [Formula: see text]/U. At low temperatures the magnetic susceptibility deviates from the Curie-Weiss temperature dependence and eventually saturates to a constant value. In contrast, Pu6W4Al43 displays nearly temperature independent Pauli paramagnetism for all temperatures, as would be expected if the 5f -electrons are delocalized. The electrical resistivity for U6W4Al43 increases slightly with the decreasing temperature, suggesting that it is dominated by f -electronic hybridization effects and disorder scattering that originates from the W/Al site interchange. Specific heat measurements for U6W4Al43 further reveal an enhanced electronic Sommerfeld coefficient that is consistent with a moderately enhanced charge carrier effective mass. Together these measurements expose these materials as hosts for unstable f -electron magnetism, where the novel cage-like structures control the phenomena through the spacing between the A ions. Through this combination of mild magnetism, the low cost elements of the Al-W cages, and chemical tunability that has been shown for related materials in the same structure, the A 6W4Al43 compounds emerge as promising nuclear waste-forms for transuranics, while the wider family of materials makes an appealing environment for studying f -electron physics in a novel structure.

Clonidine pharmacokinetics in pregnancy.

The objective of this study was to determine the pharmacokinetic parameters of clonidine during pregnancy compared with previously published data in nonpregnant subjects. Serial blood and urine samples were collected in 17 women during mid to late pregnancy over one steady-state dosing interval to determine clonidine noncompartmental pharmacokinetic parameters (n = 17) and creatinine clearance. In six of these pregnant subjects, maternal and umbilical cord (venous and arterial) plasma samples were collected at the time of delivery for measurement of clonidine concentrations. Clonidine apparent oral clearance was found to be 440 +/- 168 ml/min during pregnancy compared with 245 +/- 72 ml/min as previously reported in nonpregnant subjects (p < 0.0001) (Cunningham et al., 1994). There was a strong correlation (r = 0.82, p < 0.001) between clonidine renal clearance, adjusted for variation in glomerular filtration rate, and urine pH. Umbilical cord to maternal plasma clonidine concentration ratios were 1.0 +/- 0.1 (arterial) and 1.0 +/- 0.1 (venous). In conclusion, clonidine is cleared more rapidly in pregnant women than in nonpregnant subjects. At the time of delivery, the fetus is exposed to similar plasma clonidine concentrations as the mother.

Contribution of itraconazole metabolites to inhibition of CYP3A4 in vivo.

Itraconazole (ITZ) is metabolized in vitro to three inhibitory metabolites: hydroxy-itraconazole (OH-ITZ), keto-itraconazole (keto-ITZ), and N-desalkyl-itraconazole (ND-ITZ). The goal of this study was to determine the contribution of these metabolites to drug-drug interactions caused by ITZ. Six healthy volunteers received 100 mg ITZ orally for 7 days, and pharmacokinetic analysis was conducted at days 1 and 7 of the study. The extent of CYP3A4 inhibition by ITZ and its metabolites was predicted using this data. ITZ, OH-ITZ, keto-ITZ, and ND-ITZ were detected in plasma samples of all volunteers. A 3.9-fold decrease in the hepatic intrinsic clearance of a CYP3A4 substrate was predicted using the average unbound steady-state concentrations (C(ss,ave,u)) and liver microsomal inhibition constants for ITZ, OH-ITZ, keto-ITZ, and ND-ITZ. Accounting for circulating metabolites of ITZ significantly improved the in vitro to in vivo extrapolation of CYP3A4 inhibition compared to a consideration of ITZ exposure alone.

Importance of amine pKa and distribution coefficient in the metabolism of fluorinated propranolol derivatives. Preparation, identification of metabolite regioisomers, and metabolism by CYP2D6.

A series of 1"-mono-, di-, and trifluorinated analogs of propranolol and related steric congeners was prepared, and their metabolism was examined in recombinant-expressed CYP2D6. The structural changes in this series of compounds, principally added fluorines and methyl groups in the 1"-position of the N-isopropyl group, provided compounds that varied in pK(a) by more than 5 log units and also varied in lipophilicity and in steric size. Products of both aromatic hydroxylation and N-dealkylation were observed in the metabolic experiments. The regiochemistry of aromatic hydroxylation at the 4'- and 5'-positions was assigned based on high-pressure liquid chromatography, fluorescence, and mass spectral characteristics of the products and standards. Correlations of the metabolic kinetic parameters K(m) and catalytic efficiency (k(cat)/K(m)) with substituent parameters of the added groups showed that increased basicity (higher pK(a) values) was associated with increased enzyme affinity (low K(m) values) and increased catalytic efficiency. More basic methyl-substituted compounds showed higher affinities for CYP2D6 than the structurally analogous less basic fluorinated congeners, indicating the decrease in affinity of the fluorinated compounds was not due to the size of the N-alkyl substituent. Correlations with log D reflected the degree of ionization and showed that the less lipophilic substrates (more basic compounds) had higher affinity for CYP2D6. These results are consistent with the proposal in the literature that ion pairing of the protonated amine of the substrate with Asp301 in the active site of CYP2D6 is very important to substrate affinity.

Importance of amine pKa and distribution coefficient in the metabolism of fluorinated propranolol analogs: metabolism by CYP1A2.

A series of 1"-mono-, di-, and trifluorinated analogs of propranolol and related steric congeners was prepared, and their metabolism was examined with recombinant-expressed CYP1A2. The structural changes in this series of compounds, principally added fluorines and methyl groups in the 1"-position of the N-isopropyl group, provided compounds that varied in pK(a) by more than 5 log units, in log D by 3 log units, and in size of the added substituents. N-Dealkylation and aromatic hydroxylation (formation of the 4'- and 5'-regioisomers) were catalyzed by CYP1A2. Correlations of the metabolic kinetic parameters K(m) and catalytic efficiency (k(cat)/K(m)) with physicochemical properties pK(a) and log D showed that increased lipophilicity (higher log D values) was associated with increased affinity (lower K(m)) and increased catalytic efficiency for CYP1A2. Comparison of log K(m) and log k(cat)/K(m) with pK(a) showed that the less basic analogs had higher affinities and increased catalytic efficiencies. The changes associated with pK(a) reflect increased lipid partitioning of substrate (increased log D) caused by an increase in the proportion of nonionized substrate. Increased steric bulk in the N-substituent alone did not decrease substrate affinity for CYP1A2 but did increase the amount of aromatic hydroxylation versus N-dealkylation. Removal of the hydroxyl group from the propanolamine side chain of propranolol resulted in a similar change in regioselectivity of metabolism.

Carbinolamines, imines, and oxazolidines from fluorinated propranolol analogs. (19)F NMR and mass spectral characterization and evidence for formation as intermediates in cytochrome P450-catalyzed N-dealkylation.

Formation of carbinolamine, imine, and oxazolidines from the reactions of desisopropylpropranolol (5), its O-methyl ether (10), and 3-(1-naphthoxy)propylamine (11) with trifluoroacetone and trifluoroacetaldehyde methyl hemiacetal was investigated by (19)F NMR and tandem mass spectrometry. Products from the metabolism of the related secondary amine substrates trifluoropropranolol (7), its O-methyl ether (23), and its N-trifluoroethyl-O-methyl ether analog (24) in the presence of rat liver microsomes and CYP1A2 were examined to determine whether these species were formed. The (19)F NMR experiments showed the presence of carbinolamine and imine species from these primary amines and fluorinated carbonyl compounds in solution. Mass spectral experiments under atmospheric pressure chemical ionization and electrospray ionization-ion trap conditions showed formation of imine metabolites (and/or oxazolidine from 7) as well as products of N-dealkylation and aromatic hydroxylation when the secondary amine substrates were incubated with rat liver microsomes or CYP1A2. In spite of mass spectral evidence for these imines as metabolites, we were unable to detect the carbinolamines under the conditions used in these studies. Their presence is inferred from the results of the (19)F NMR experiments.

Mass spectral fragmentation pathways of propranolol related beta-fluorinated amines studied by electrospray and electron impact ionization.

Propranolol, its 1"-mono-, di-, and trifluorinated analogs, and other related compounds were analyzed under electrospray ionization ion trap collision-induced dissociation (ESI-CID) and electron impact (EI) conditions. Interesting trends were observed in the fragment ions formed in both cases. Under ESI conditions, the abundances of product ions easily explained by protonation on the amine nitrogen decreased relative to the abundances of those formed from the ether-protonated species as the number of fluorines increased from zero to three. Under EI conditions, the distribution of fragment ions was shifted away from those arising from a nitrogen-centered cation radical and toward those arising from an ether oxygen-centered cation radical. The changes observed in apparent molecular sites of protonation and of ion radical formation in the mass spectra are consistent with the electron-withdrawing effects of the sequentially added fluorines. These effects are correlated with changes in solution phase pK( a)'s of the fluorinated amines.

Fragmentation pathways of selectively labeled uropranolol using electrospray ionization on an ion trap mass spectrometer and comparison with ions formed by electron impact.

Propranolol, deuterium- and 18O-labeled propranolol and related compounds were analyzed using an ion trap mass spectrometer equipped with a modified Finnigan API electrospray interface. Sequential product ion (MSn) experiments were used to elucidate fragmentation pathways for these compounds. The observed ions were compared to those observed under electron impact (EI) conditions. The electrospray ionization (ESI) ion trap spectra, as well as the EI spectra, afford useful information to allow assignments of most product ions, many of which retain portions of the aliphatic three-carbon side chain.

Anorexic eating attitudes and behaviors of male and female college students.

This study examined gender differences in eating attitudes and behaviors in a sample of 471 undergraduate college students. The prevalence of symptomatology indicative of anorexia was determined using the Eating Attitudes Test (EAT-26). In addition, the family climate, parent-child dynamics, and self-concept of students with and without maladaptive eating attitudes and behaviors were compared, and the relationship between eating attitudes/behaviors and current psychological distress was examined. Anorexic symptomatology was found for 20% of the females and 10% of the males. In general, students without symptomatic attitudes and behaviors had a more positive self-concept and reported less psychological distress than did those with eating disturbances. The findings suggest that eating problems may be more prevalent among males than previously estimated.

HIV antibody testing: Genito-Urinary Clinic or additional site same-day testing service.

It has been suggested that different groups of individuals, possibly those at greater risk, may choose to attend anonymous HIV services not attached to Genito-Urinary Medicine Clinics. This paper reports the results of a comparative study of documented sociodemographic profile and risk category for individuals having HIV antibody tests at a Genito-Urinary Medicine Clinic and at an additional site same-day HIV antibody testing service not attached to a Genito-Urinary Medicine Clinic but within the same hospital. A retrospective case record analysis for 12 months from 1.10.93 to 30.9.94 was performed. During the 12-month study period 954 people had HIV testing at the additional site HIV antibody testing service and 803 had HIV antibody testing at the Genito-Urinary Medicine Clinic. Of those attending the additional site testing service 218 (22.9%) were homosexual/bisexual males as compared with 128 (15.9%) of the Genito-Urinary Medicine Clinic attendees (p < 0.01). A total of 22 (2.3%) of the individuals attending the additional site service gave a history of sexual contact in Africa as compared with 52 (65%) attending the Genito-Urinary Medicine Clinic (p < 0.001). There was no significant difference in the gender or age of those having HIV antibody tests at the two locations (p = 0.82 and p = 0.39 respectively). Four hundred and seventeen (52%) of the tests performed at the Genito-Urinary Medicine Clinic were performed on those who had not already decided to have a test before attending the clinic. Of those individuals who had decided to have a test before attending, 2.5 times as many attended the Same-Day Service as attended the Genito-Urinary Medicine Clinic (954 additional site attenders compared with 384 Genito-Urinary Medicine Clinic attenders). The results suggest that to optimize patient choice and benefit from a HIV antibody testing service this should be available at both Genito-Urinary Medicine Clinics and at additional site testing services.

(E)- and (Z)-7-arylidenenaltrexones: synthesis and opioid receptor radioligand displacement assays.

The E-isomer of 7-benzylidenenaltrexone (BNTX, la) was reported by Portoghese as a highly selective delta-opioid antagonist. The corresponding Z-isomer 1b was not readily available through direct aldol condensation of naltrexone (6) with benzaldehyde. Using the photochemical methods employed by Lewis to isomerize cinnamamides, we have obtained Z-isomer 1b in good yield from E-isomer 1a. A series of (E)- and (Z)-7-arylidenenaltrexone derivatives was prepared to study the effect of larger arylidene groups on opioid receptor affinity in this series. By aldol condensation of naltrexone (6) with benzaldehyde, 1-naphthaldehyde, 2-naphthaldehyde, 4-phenylbenzaldehyde, and 9-anthracaldehyde, the (E)-arylidenes were readily obtained. Photochemical isomerization afforded the corresponding Z-isomers. These compounds were evaluated via opioid receptor radioligand displacement assays. In these assays, the Z-isomers generally had higher affinity and were more delta-selective than the corresponding E-isomers. The (Z)-7-(1-naphthylidene)naltrexone (3b) showed the greatest selectivity (delta:mu ratio of 15) and highest affinity delta-binding (Ki = 0.7 nM). PM3 semiempirical geometry optimizations suggest a significant role for the orientation of the arylidene substituent in the binding affinity and delta-receptor selectivity. This work demonstrates that larger groups may be incorporated into the arylidene portion of the molecule with opioid receptor affinity being retained.

Irreversible binding of N-methyl-N-[(1S)-1-(4-isothiocyanatophenyl)-2-(1-pyrrolidinyl)ethyl-3,4 -dichlorophenylacetamide to the cloned rat kappa opioid receptor.

N-Methyl-N-[(1S)-1-(4-isothiocyanatophenyl)-2-(1-pyrrolidinyl)ethyl-3,4- dichlorophenylacetamide (MITPD), is an isothiocyanate derivative of the kappa agonist ICI-199,441. In this study, interaction of MITPD with cloned mu, delta, and kappa opioid receptors was characterized. MITPD inhibited [3H]diprenorphine binding to kappa receptors with high affinity and with approximately 700- and approximately 870-fold selectivity over mu and delta receptors. Pretreatment with MITPD followed by extensive washing reduced kappa receptor binding with an IC50 value of 3.7 nM, but did not affect mu or delta binding at < or = 0.1 microM. Preincubation with 1 microM MITPD abolished [3H]diprenorphine binding, while pretreatment with 1 microM ICI-199,441 increased Kd of [3H]diprenorphine binding with no change in Bmax. Thus, MITPD is a selective kappa irreversible ligand. The region of the kappa receptor that conferred selectivity for MITPD was determined by examining its binding to four mu/kappa chimeras. IC50 values of MITPD for inhibition of [3H]diprenorphine binding were determined to be 430 nM for Chimera III (kappa1-141/mu151-398), 1.8 nM for Chimera IV (mu1-150/kappa142-380), 40 nM for Chimera XI (mu1-268/kappa263-380) and 14 nM for Chimera XII (kappa1-262/mu269-398). Pretreatment with MITPD followed by extensive washing reduced binding to chimera IV with an IC50 value of 75 nM, but did not affect III, XI or XII binding (IC50 >1 microM). Thus, the region from the third transmembrane helix to the C-terminus of the kappa receptor is important for the binding of MITPD.

Regioselectivity and enantioselectivity of metoprolol oxidation by two variants of cDNA-expressed P4502D6.

PURPOSE: The oxidative metabolism of metoprolol was investigated in two human lymphoblastoma cell-lines transfected with variants of cDNA for cytochrome P4502D6. METHODS: The regioselective and enantioselective features of the oxidations of deuterium-labeled pseudoracemic metoprolol were characterized by GC/MS analysis of the substrate and products. RESULTS: There were significant differences between the two P4502D6 variants in the formation kinetics of O-demethylmetoprolol and alpha-hydroxymetoprolol. The h2D6-Val microsomes highly favored the formation of the O-demethylmetoprolol regioisomer 6.3:1 and 2.8:1, respectively from (R)-metoprolol-d0 and (S)-metoprolol-d2, while the corresponding ratios for h2D6v2 microsomes were much lower. For both variants, O-demethylmetoprolol formation favored the (R)-substrate 1.5 to 2-fold, while alpha-hydroxymetoprolol formation was non-enantioselective. Similar Km values of metoprolol oxidation, 10-20 microM, were observed for the two microsomal preparations. CONCLUSIONS: The regioselectivity, enantioselectivity, and Km values for the h2D6-Val microsomes resemble those observed for the native P4502D6 in human liver microsomes, whereas the h2D6v2 microsomes deviated remarkably in regioselectivity.

Regioselective and stereoselective oxidation of metoprolol and bufuralol catalyzed by microsomes containing cDNA-expressed human P4502D6.

Regioselective and stereoselective oxidations of pseudoracemic metoprolol, (R)-bufuralol, and (S)-bufuralol by microsomes of h2D6v2 cells--a human lymphoblastoma cell line transfected with a cytochrome P4502D6 expression system--were examined. The formation kinetics of O-demethylmetoprolol and alpha-hydroxymetoprolol were characterized in five different lots of the cDNA-expressed P4502D6. Comparison of the Vmax/KM values indicated that formation of the products from (R)-metoprolol was preferred. Although the favored regiomer overall was O-demethylmetoprolol, the regioselectivity for O-demethylation of metoprolol by the cDNA-expressed enzyme was several-fold less than that observed for the P4502D6 enzyme in human liver microsomes at 20 microM pseudoracematic metoprolol concentration. Oxidation of (R)-metoprolol produced more O-demethylmetoprolol than alpha-hydroxymetoprolol; however, for (S)-metoprolol-d2, a slight preference for alpha-hydroxylation was observed. The O-demethylation and alpha-hydroxylation of metoprolol were inhibited at low microM concentrations of (+/-)-verapamil, a known inhibitor of metoprolol oxidation. (R)- and (S)-Bufuralol were oxidized to their respective diastereomeric 1"-hydroxybufuralols by all 4 lots of h2D6v2 microsomal preparations. Diastereomeric (1'R)-hydroxybufuralols were formed in twice the amount as the hydroxylated diastereomers of (1'S)-products. Product stereoselectivity was observed for the (1'R,1"S)- and (1'S,1"R)-isomers. Although the observed enantioselectivity and diastereoselectivity of the bufuralol oxidation seem to be consistent with those previously reported for human liver microsomes, the regioselectivity of the metoprolol oxidations is unexpectedly low.

Isothiocyanate-substituted benzyl ether opioid receptor ligands derived from 6 beta-naltrexol.

A series of regioisomeric substituted 6-O-benzyl ethers of 6 beta-naltrexol (12) in which isothiocyanate groups were attached directly to or one carbon removed from the aromatic ring of the benzyl group were prepared. These agents were prepared to obtain electrophilic opioid ligands potentially useful in the characterization of opioid receptors and drug-receptor interactions. Preparation of these ligands was accomplished from 3-O-trityl-6 beta-naltrexol (13) via phase transfer-catalyzed alkylation of the regioisomeric o-, m-, and p-nitrobenzyl halides and the o-, m-, and p-cyanobenzyl halides. The intermediates were deprotected and reduced, and formation of the isothiocyanates from the corresponding amines completed the synthesis. The ligands (6-11) were tested in radioligand displacement assays in guinea pig brain homogenate for opioid receptor binding affinity and irreversibility. All six of the isothiocyanates demonstrated significant affinity in the displacement assays for all three opioid receptors. They also appeared to be irreversibly bound at each of the receptor types. Compound 6, the o-isothiocyanatobenzyl ether analog, had the highest affinity, and it demonstrated significant irreversibility at very low concentration. It appears to be suitable for further investigation.

Synthesis and opioid receptor affinity of a series of aralkyl ethers of 6 alpha- and 6 beta-naltrexol.

A series of 6-O-ethers of 6 beta- and 6 alpha-naltrexol (6 and 7) were prepared to examine the effect of large aralkyl groups on affinity of the ligands for opioid receptors. The affinities of the 6 beta- and 6 alpha-O-ether with benzyl, biphenylmethyl, 1- and 2-naphthylmethyl, and 9-anthracylmethyl groups were determined. Preparation of the ligands was accomplished from suitably 3-O-protected derivatives of 6 and 7 by phase transfer catalyzed alkylation using aralkyl halides, followed by deprotection. Both 3-O-trityl and -benzyl protecting groups were used. In radioligand displacement assays, compounds from the 6 alpha-O ether series had higher affinity than the analogous diastereomers in the 6 beta-O series, with few exceptions. In the 6 alpha-O series, the benzyl ether (29) and the biphenylmethyl ether (30) had the highest affinity, similar to naltrexone. In the 6 beta-O series, the benzyl ether had the highest affinity. The larger aralkyl ethers had slightly less affinity. Large lipophilic 6 beta-O- and 6 alpha- O-aralkyl groups are readily accommodated in the drug-receptor interaction.

Isothiocyanate-substituted kappa-selective opioid receptor ligands derived from N-methyl-N-[(1S)-1-phenyl-2-(1-pyrrolidinyl)ethyl] phenylacetamide.

The synthesis of isothiocyanate-substituted kappa-selective opioid ligands derived from N-methyl-N-[(1S)-1-phenyl-2-(1-pyrrolidinyl)ethyl]ethyl]phenylacetami de (8) and their effects in radioligand displacement assays are reported. Ligands 3-5 with the S-absolute configuration were prepared with the isothiocyanate functionality at the 2-, 3-, and 4-positions in the phenylacetamide aromatic ring. The 2-isothiocyanato-4,5-dichlorophenylacetamide 6 was prepared to evaluate the effect of 4,5-dichloro substitution in the same aromatic ring as the 2-isothiocyanate function. N-Methyl-N-[(1S)-1-(4-isothiocyanatophenyl)-2-(1-pyrrolidinyl) ethyl]-3,4-dichlorophenylacetamide (7), with the 4-isothiocyanate function in the 1-phenyl ring, was prepared for comparison with the other compounds in the series. Of the prepared ligands, 7 and 8 (IC50s congruent to 1.4-1.8 nM) were approximately equal in affinity with 2 (ICI-199,441), followed by 3 and 6. All of these compounds were more kappa-selective than 2, as well. The binding characteristics of 8 show that the previously reported 4,5-dichloro substitution is not required for high affinity and kappa-selectivity. All of the synthesized isothiocyanate-substituted ligands irreversibly inhibited radioligand binding to guinea pig brain membrane preparations, including compound 2 (ICI-199,441) which had no isothiocyanate functionality.