Tumor growth in the pelvis with nerve involvement causes severe pain which is notoriously resistant to pharmacological treatment. Chordotomy is a classical method for the relief of pain. This is a retrospective study of 24 chordotomy cases, operated on at the department of Neurosurgery, and independently evaluated at the department of Gynecologic Oncology. Initially 19 patients (79%) were painfree whereas 4 patients (17%) had only moderate or no relief following the operation (one not evaluable). 10 patients remained free of pain until death. There were no serious complications. Possible causes of pain relapse are analysed. We conclude that chordotomy is worth consideration when facing severe pelvic cancer pain.
The salicylamide NCQ 298, (S)-3-iodo-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5,6-dimethoxysalicylami de (4), binds with a high affinity and selectivity to central dopamine D-2 receptors. In the present paper the synthesis of NCQ 298 and the efficient labelling both with 123I and 125I are described. The unlabelled NCQ 298 was synthesized by iodination of (S)-N-[(1-ethyl-2-pyrrolidinyl)methyl]-2,5,6-trimethoxybenzamide followed by demethylation with boron tribromide, which produced 4 and the regioisomer 5 in a ratio of 82:18. The two isomeric salicylamides were separated by radial chromatography and tested for their abilities to inhibit the binding of [3H]raclopride to rat striatal membranes in vitro in relation to some representative salicylamides. The 5,6-dimethoxysalicylamide 4 (NCQ 298) was found to be considerably more active than the corresponding 6-methoxysalicylamide 10 (FLA 961 or IBZM). The radioligands [123I]NCQ 298 and [125I]NCQ 298 were prepared in a carrier-free form from the corresponding desiodo compound by the chloramine-T protocol and isolated by semipreparative HPLC. The total radiochemical yields of [123I]NCQ 298 and [125I]NCQ 298 (based on [123I]- and [125I]iodide and decay-corrected) were 88% and 93%, respectively, with a radiochemical purity of greater than 99%. [125I]NCQ 298 will be studied to evaluate its potential as a radioligand in studies requiring a high specific activity, selectivity and high potency to label dopamine D-2 receptors. [123I]NCQ 298 has potential as a radioligand for the in vivo examination of central dopamine D-2 receptors in human brain by Single Photon Emission Computed Tomography (SPECT).
Ingenol mebutate gel (Picato®, LEO Pharma A/S) is approved for the field treatment of actinic keratosis and is characterized by high sustained clearance of actinic lesions. The inherent propensity of ingenol mebutate towards chemical rearrangement necessitates refrigeration of the final product. We sought to identify novel ingenol derivatives with enhanced chemical stability and similar or improved in vitro potency and in vivo efficacy. A number of ingenol esters were synthesized with full regiocontrol from ingenol. Chemical stability was determined in aqueous buffer at physiological pH and hydroalcoholic gel at lower pH. Acute cytotoxicity was determined in HeLa or HSC-5 cells. Keratinocyte proliferation, viability and caspase 3/7 activation was measured in primary epidermal keratinocytes. Relative gene expression levels were determined by real-time quantitative PCR. Evaluation of in vivo tumor ablating potential was performed in the murine B16 melanoma mouse model and in the UV-induced skin carcinogenesis model in hairless SKH-1 mice following topical treatment for two consecutive days with test compounds formulated at 0.1% in a hydroalcoholic gel. This work resulted in the identification of ingenol disoxate (LEO 43204) displaying increased stability in a clinically relevant formulation and in aqueous buffer with minimal pH-dependent acyl migration degradation. Ingenol disoxate exhibited a significantly higher cytotoxic potency relative to ingenol mebutate. Likewise, cell growth arrest in normal human keratinocyte was more potently induced by ingenol disoxate, which was accompanied by protein kinase C dependent transcription of markers of keratinocyte differentiation. Most notably, ingenol disoxate possessed a superior antitumor effect in a B16 mouse melanoma model and significantly increased median survival time relative to ingenol mebutate. A significant effect on tumor ablation was also observed in a murine model of ultraviolet irradiation-induced skin carcinogenesis. These data illustrate that the favorable in vitro and in vivo pharmacological properties driving ingenol mebutate efficacy are either preserved or improved in ingenol disoxate. In combination with improved chemical stability to potentially facilitate storage of the final product at ambient temperatures, these features support further development of ingenol disoxate as a convenient and efficacious treatment modality of non-melanoma skin cancers. LEO Pharma A/S.
The X-ray structures of two new 2,6-disubstituted benzamides, i.e., remoxipride hydrochloride monohydrate [-)-(S)-3-bromo-N-[(1-ethyl-2-pyrrolidinyl)methyl]-2,6-dimethoxybenza mide hydrochloride monohydrate) and FLA 797 [-)-(S)-3-bromo-N-[(1-ethyl-2-pyrrolidinyl)methyl]-6-methoxysalicylamide ), have been determined as well as the distribution coefficients. The difference in dopamine receptor blocking activity is discussed in terms of lipophilicity and solid state conformations of the two benzamides. The major difference between the solid state conformations lies in the orientation of the carboxamide moiety. In remoxipride the carbonyl group is oriented almost perpendicularly to the benzene ring, thus preventing the formation of a hydrogen-bonded pseudo-ring between the amide hydrogen and the methoxy group found in other types of o-methoxybenzamides. In FLA 797, however, this pseudo-ring is present in the planar conformation of the salicylamide moiety. This conformation is further stabilized by a hydrogen bond between the phenol group and the carbonyl oxygen. The side chain in remoxipride adopts an extended conformation in contrast to FLA 797, where the side chain has a folded conformation. The crystal structures are related to current topographic dopamine receptor models developed from more rigid antidopaminergic compounds. Based on these comparisons, it is suggested that benzamides having an N-ethyl-2-pyrrolidinylmethyl side chain interact with the receptor in the folded conformation. The binding affinity is thought to be further increased by the planar conformation of the salicylamide moiety present in FLA 797, which permits an efficient pi-pi stacking interaction.
This paper reviews the development of 2,6-dioxygenated benzamides such as remoxipride and various salicylamides (raclopride, eticlopride) into other types having a 5,6-dioxygenated benzamide moiety. The structural, conformational and stereochemical aspects on the structure-activity relationships are discussed. The three side chain classes (S)-2-pyrrolidinylmethyl-, (R)-2-pyrrolidinylmethyl- and 4-piperidinylbenzamides have different requirements on aromatic substituents and side chain conformations. Besides, the latter two types demand lipophilic nitrogen substituents (arylalkyl) for dopamine D2 receptor affinity. This indicates that they have different pharmacophoric requirements that might prove useful in investigations on dopamine D2 receptor subtypes. The 3-substituted 5,6-dimethoxysalicylamides (e.g. FLB 463 and NCQ 298) and the 3-substituted 5,6-dimethoxybenzamides (e.g. FLB 457 and NCQ 219) constitute highly potent and selective dopamine D2 antagonists in vitro as well as in vivo. Both types of benzamides have been developed as radioligands for receptor binding (125I, 3H), PET (11C, 18F) and SPECT (123I) studies which fully take advantage of the favourable properties. Thus, NCQ 298, NCQ 115, FLB 457 and NCQ 616 are such potent and selective ligands, which are suitable for further receptor characterization and studies on dopamine D2 mediated responses.
Several metabolites of (Z)-3-(4-bromophenyl)-N,N-dimethyl-3-(3-pyridyl)allylamine (zimelidine) were isolated from urine of rat and dog after administration of the 14C-labelled drug. The major metabolic routes found in these species involve oxidations at both the aliphatic and aromatic nitrogen, N-demethylations and deamination of the aliphatic nitrogen. The major excretion products in urine from both rat and dog were the N-oxide of zimelidine, the deamination product 3-(4-bromophenyl)-3-(3-pyridyl)-acrylic acid and its N-oxide. Apparently, there are only minor differences between rat and dog in the metabolism of zimelidine. The N-oxide of zimelidine and the acrylic acid derivative were also identified in a human urine sample. Zimelidine was labelled with 14C in the allylic position. Most of the metabolites were synthesized in pure diastereomeric form and their configuration were shown by UV and 1H-NMR.
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