4-Fluoro-N-{2-[4-(6-trifluoromethylpyridin-2-yl)piperazin-1-yl]ethyl}benzamide is a full 5-HT1A agonist with high affinity (pK(i) = 9.3), selectivity and a c log P of 3.045. The corresponding PET radioligand 4-[F-18]fluoro-N-{2-[4-(6-trifluoromethylpyridin2-yl)piperazin-1-yl]ethyl}benzamide was synthesized by nucleophilic aromatic substitution on the nitro precursor. The fluorinating agent K[F-18]F/Kryptofix 2.2.2 was both dried (9 min, 700 W) and incorporated in the precursor (5 min, 700 W) using a commercially available microwave oven. In a total synthesis time of 60 min, an overall radiochemical yield of 18% (SD = 5, n = 7, EOS) was obtained. Radiochemical purity was always higher than 99% and specific activity always higher than 81.4 GBq/mumol (2.2 Ci/mumol). Initial brain uptake in mice was 2.19% ID (5.47% ID/g, 2 min) but decreased rapidly (0.17% ID, 0.45% ID/g (60 min)). During the first 20 min p.i., radioactivity concentration of the brain was significantly higher than that of blood demonstrating good brain entry of the tracer. Copyright (C) 2004 John Wiley Sons, Ltd.

To exclude that aromatization plays a role in the estrogenic activity of tibolone, we studied the effect fibolone and metabolites on the aromatization of androstenedione and the aromatization of fibolone and its metabolites to 7alpha-methyl-17alpha-ethynylestradiol (7alpha-MEE) by human recombinant aromatase. Testosterone (T), 17alpha-methyltestosterone (MT), 19-nortestosterone (Nan), 7alpha-methyl-19-nortestosterone (MENT) and norethisterone (NET) were used as reference compounds. Sensitive in vitro bioassays with steroid receptors were used to monitor the generation of product and the reduction of substrate. LC-MSMS without derivatization was used for structural confirmation.A 10 times excess of tibolone and its metabolites did not inhibit the conversion of androstenedione to estrone by human recombinant aromatase as determined by estradiol receptor assay whereas T, MT, Nan, and MENT inhibited the conversion for 75, 53, 85 and 67%, respectively. Tibolone, 3alpha- and 3beta-hydroxytibolone were not converted by human aromatase whereas the estrogenic activity formed with the Delta(4)-isomer suggests a conversion rate of 0.2% after 120 min incubation. In contrast T, MT, Nan, and MENT were completely converted to their A-ring aromates within 15 min while NET could not be aromatized. Aromatization of T, MT, Nan and MENT was confirmed with LC-MSMS. Structure/function analysis indicated that the 17alpha-ethynyl-group prevents aromatization of (19-nor) steroids while 7alpha-methyl substitution had no effect.Our results with the sensitive estradiol receptor assays show that in contrast to reference compounds fibolone and its metabolites are not aromatized. (C) 2002 Elsevier Science Inc. All rights reserved.

4-[123I]Iodo-N-[2-[4-(6-trifluoromethyl-2-pyridinyl)-1-piperazinyl]ethyl]benzamide (1.123I), a potential SPECT 5-HT(1A) radioligand, was evaluated in vivo in rats. Biodistribution studies were performed leading to a % ID in the brain of 0.22 at 5 min p.i. No significant differences in % ID/g tissue of the different isolated brain regions (hippocampus, hypothalamus, striatum, cortex and cerebellum) could be demonstrated. Blocking experiments with 8-OH-DPAT, WAY100635 and ketanserin could not show any significant change in tracer uptake in the isolated brain regions. These data suggest that uptake in the brain does not represent binding of 1.123I to the 5-HT(1A) receptor.

There is a general need for new orally active androgens, to be used for androgen replacement therapy and male hormonal contraception. As a substitute for low levels of testosterone in hypogonadal men, therapy with the natural androgen testosterone is the first choice. However, testosterone is an androgen with a relatively low affinity for the androgen receptor. It is metabolically relatively unstable which results in poor oral bioavailability. In addition, testosterone is converted by 5α-reductase into the more potent androgen 5α-dihydrotestosterone (5α-DHT). Early attempts to prevent metabolic instability by 17α-alkylation of androgens (like introduction of 17 α-ethynyl in estrogens and progestagens) were not successful, due to liver toxicity or low androgenic activity (Vida 1969). Another approach to circumvent metabolic instability is esterification of the 17β-OH group of testosterone with long chain fatty acids. Testosterone undecanoate formulated in an oily solution (Andriol®/Andriol TestocapsTM, dissolved in oleic acid and a mixture of castor oil and polypropylene glycol laurate, respectively) is currently the only orally active testosterone derivative. This testosterone ester is hydrolysed by tissue (liver) esterases and testosterone is released (Bursi et al. 2001). However, due to the limited potency of testosterone and limited bioavailability of testosterone undecanoate, relative high doses of Andriol®/Andriol TestocapsTM are required twice a day for human androgen replacement (total dose 160–240 mg).

Abstract[18F]Org 13063 or 4‐[18F]fluoro‐N‐{2‐[4‐(6‐trifluoromethyl‐2‐pyridinyl)‐1‐piperazinyl]ethyl}benzamide was synthesized by nucleophilic aromatic substitution on the nitro precursor in a microwave oven (5 min, 700 W). Overall radiochemical yield was 20 % (EOB), chemical and radiochemical purity were respectively higher than 95 and 99 %. Specific activity was always higher than 18.5 GBq/μmol (500 mCi/μmol). Biodistribution studies in rabbits were performed leading to 0.77 % ID in the brain at 5 min p.i. Radioactivity concentration of brain was significantly higher than that of blood. However, no significant differences in % ID/g tissue of the different isolated brain regions (hippocampus, hypothalamus, striatum, cortex and cerebellum) could be demonstrated.

Although the chemical structures of the antidepressants mirtazapine and mianserin are closely related there are considerable differences in their biological properties. To find an explanation of this, various physicochemical properties of mirtazapine and mianserin were measured or calculated.Isosteric replacement of CH in mianserin by N in mirtazapine has profound effects on physicochemical properties. The charge distributions as indicated by NMR and calculated by semi-empirical quantum mechanics differ, not only for the changed aromatic A-ring (as expected), but also in other regions of the molecule. The N5 atom in particular, which is conjugated to the changed aromatic ring, is less negatively charged in mirtazapine than in mianserin. Consequently the oxidation potential of mirtazapine is significantly higher than that of mianserin. Another result of this difference in charge distribution is that the (calculated) dipole-moment vectors of the compounds are oriented roughly perpendicular to each other. The dipole moment of mirtazapine is, moreover, three times larger than that of mianserin; mirtazapine is, therefore, more polar than mianserin and this is reflected in a lower retention index. Finally, the basicity of mirtazapine, expressed as the pK(a) value, is slightly but significantly lower than that of mianserin.The observed differences between the physicochemical properties of mirtazapine and mianserin result in different interactions of these two antidepressants with macromolecules, such as receptors, transporters and metabolizing enzymes; this might explain the differences observed in pharmacological activity and metabolic and kinetic behaviour, that is, the reduced affinity for the alpha(1)-adrenoceptor and negligible noradrenaline reuptake of mirtazapine compared with mianserin.

The structural characteristics of ortho- and meta-substituted phenylpiperazines have been investigated in order to understand their actions at the serotonin 5-HT2C receptor. The crystal structures of the 4-methylated analogues of two phenylpiperazines that are already known as 5-HT2C ligands, 1-(1-naphthyl)-4-methylpiperazine (1NMP) and 1-[(3-trifluoromethyl)phenyl]-4-methylpiperazine (TFMPMP), and those of two novel 5-HT2C ligands, 1-(2-methoxyphenyl)piperazine (oMPP) and 1-(3-methoxyphenyl)piperazine (mMPP), are determined. Molecular mechanics calculations are performed to calculate the energy profiles of six phenylpiperazines for rotation about the central phenyl-nitrogen bond. The activities of several phenylpiperazines, in combination with their crystal structures and conformational characteristics, lead to the hypothesis that the conformation for which the piperazine ring and the phenyl ring are approximately co-planar should be the 5-HT2C receptor 'activating' conformation. This hypothesis is then used to predict the activities of the two novel 5-HT2C ligands oMPP and mMPP. oMPP is predicted to be an antagonist at this receptor, whereas mMPP is predicted to be an agonist. As this prediction was confirmed by in vitro and in vivo tests, the proposed conformation is very likely to be responsible for the activation of the 5-HT2C receptor.

The antipsychotics currently used need to be improved, both in terms of efficacy and side-effect profile. In particular, the treatment of negative symptoms of schizophrenia and the occurrence of extrapyramidal side-effects need to be addressed. The high affinity for the 5-HT2A receptor of the atypical antipsychotic clozapine has renewed the interest in antagonists for this receptor. Several lines of evidence point towards a possible role of 5-HT2A receptors in the pathophysiology and treatment of schizophrenia. However, as the cause of schizophrenia is unknown the success of any approach based upon a specific biochemical mechanism can only be established in the clinic. Therefore, the real significance of 5-HT2A receptor antagonists for antipsychotic treatment will only become clear when data become available on the clinical efficacy of selective 5-HT2A receptor antagonists.In this manuscript the highlights published in the past decade are reviewed. Clinical and experimental data which support the rationale for 5-HT2A antagonists are listed. Next, the 5-HT2 receptor subtypes and regulation and structure of the 5-HT2A receptor are described. The 5-HT2A antagonists on the market or under (pre)clinical development as antipsychotics are listed. Finally, the major chemical classes of 5-HT2A receptor antagonists with relevance to psychosis are discussed.

The clean and efficient cleavage of N-benzyl linked tertiary amines from a solid support (e.g. 4) by treatment with α-chloroethyl chloroformate (ACE-Cl) / methanol to yield secondary amines 7 is described. This allows the solid-phase synthetic transformation of the secondary amine 2 into 7. When the Merrifield resin 1 is used the N-tethered amine-polymeric matrix ensemble is stable towards a wide variety of reaction conditions.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTProspects for Improved AntidepressantsC. L. E. Broekkamp, D. Leysen, B. W. M. M. Peeters, and R. M. PinderCite this: J. Med. Chem. 1995, 38, 23, 4615–4633Publication Date (Print):November 1, 1995Publication History Published online1 May 2002Published inissue 1 November 1995https://pubs.acs.org/doi/10.1021/jm00023a001https://doi.org/10.1021/jm00023a001research-articleACS PublicationsRequest reuse permissionsArticle Views530Altmetric-Citations84LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-Alertsclose Get e-Alerts

Phosphorous pentoxide is the catalyst of choice for the facile conversion of primary amines, aromatic amines, sulfonamides and primary amides into the corresponding N-substituted pyrroles from 2,5-dimethoxytetrahydrofuran.

In the pursuit of biologically active compounds we required as a key intermediate 2,3-dihydro-1,3-benzoxaz-4-ones having a halomethylene moiety at C(2), i.e. 3 (R2= H or alkyl, R3=CH2X). The standard procedure for the preparation of this class of compounds is the condensation of salicylamide derivatives 1 with the proper aldehydes1-5 and ketones5,6. Usually, hydrochloric acid or sulphuric acid is used as catalyst and the water formed is cocommittently removed using a dehydrating agent or by azeotropic destillation7. These procedures did not serve our purpose as the required alpha-substituted aldehyde or ketone as such is unstable under the conditions employed. Here we report that employment of acetals and ketals 2 affords the desired compound 3; yields are appreciable when the proper reaction conditions are used.