The naphthalene analog of medetomidine (1), 4-[1-(1-naphthyl)ethyl]-1H- imidazole (2), is a highly potent, selective alpha 2-adrenoceptor agonist. We have initiated a structure-activity relationship study of the replacement of the methyl group on the carbon bridge between the naphthalene and imidazole rings of 2 with a hydrogen, hydroxy, methoxy, carbonyl, or trifluoromethyl group and compared their biological activities with medetomidine 1 and the optical isomers of 2. Analogs of 2 were antagonists of alpha 2A-adrenoceptor-mediated human platelet aggregation and agonists on alpha 1- and alpha 2-adrenoceptors in guinea pig ileum. The rank order and potencies of these analogs on platelets (alpha 2A-subtype) and guinea pig ileum (alpha 1-subtype) were nearly the same, whereas racemic and S-(+)-2, desmethyl, and hydroxy analogs were potent agonists on alpha 2-adrenoceptors in guinea pig ileum. With the exception of the desmethyl analog 5, none of the other analogs were as potent as the parent drug 2 on alpha 2A- (human platelets), alpha 1- (guinea pig ileum), or alpha 2- (guinea pig ileum) adrenergic receptor systems. As with analog 2, the desmethyl- and methoxy-substituted analogs retained a greater alpha 2/alpha 1-selectivity in both functional (agonist activity) and biochemical (receptor displacement) studies. Receptor binding studies indicate that S-(+)-2 possessed greater affinity than the R-(-)-isomer on both alpha 1- and alpha 2-adrenoceptors in rat brain. In addition, R-(-)-2 did not show agonist activity in alpha 2-adrenoceptors of guinea pig ileum and was 10-fold more potent than S-(+)-2 as an antagonist of alpha 2A-adrenoceptors in human platelets. Thus, the nature of the substituent and the chirality at the carbon bridge between the naphthalene and imidazole rings play an important role in maintaining potent alpha 2-adrenoceptor activity and high alpha 2/alpha 1-selectivity within the 4-substituted imidazole class.

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Recently we synthesized a naphthalene analog of medetomidine, 4-[1-(1-naphthyl)ethyl]-1H-imidazole hydrochloride (1), and found it to be highly potent in adrenergic systems. The separation of optical isomers of this naphthalene analog was achieved by using the isomers of tartaric acid. The optical purities of the isomers were determined by HPLC using a chiral column. Using X-ray analysis the (+)-isomer was determined to have the S absolute configuration. It has been reported that the (+)-isomer of medetomidine (2) is the most potent enantiomer on alpha 2-adrenergic receptors. There were both qualitative and quantitative differences in biological activities of the optical isomers of 1 in alpha 1- and alpha 2-adrenergic receptor systems of guinea pig ileum and human platelets. (+)-(S)-1, but not (-)-(R)-1 was a selective agonist of alpha 2-mediated responses in ileum whereas (-)-(R)-1 was more potent than (+)-(S)-1 as an inhibitor of alpha 2-mediated platelet aggregation.

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTDesign and synthesis and propranolol analogs as serotonergic agents [Erratum to document cited in CA110(19):172847n]M. Edward Pierson, Robert A. Lyon, Milt Titeler, Steven B. Schulman, Paul Kowalski, and Richard A. GlennonCite this: J. Med. Chem. 1990, 33, 4, 1270Publication Date (Print):April 1, 1990Publication History Published online1 May 2002Published inissue 1 April 1990https://pubs.acs.org/doi/10.1021/jm00166a029https://doi.org/10.1021/jm00166a029research-articleACS PublicationsRequest reuse permissionsArticle Views103Altmetric-Citations-LEARN 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

With [3H]ketanserin as the radioligand, structure-affinity relationships (SAFIRs) for binding at central 5-HT2 serotonin receptors (rat frontal cortex) were examined for a series of 27 4-substituted 1-(2,5-dimethoxyphenyl)-2-aminopropane derivatives (2,5-DMAs). The affinity (Ki values) ranged over a span of several orders of magnitude. It appears that the lipophilic character of the 4-position substituent plays a major role in determining the affinity of these agents for 5-HT2 receptors, 2,5-DMAs with polar 4-substituents (e.g. OH, NH2, COOH) display a very low affinity (Ki greater than 25,000 nM) for these receptors, whereas those with lipophilic functions display a significantly higher affinity. The results of these studies prompted us to synthesize and evaluate examples of newer lipophilic derivatives and several of these (e.g. n-hexyl, n-octyl) bind with very high (Ki values = 2.5 and 3 nM, respectively) affinities at central 5-HT2 sites. Although, 2,5-DMAs are generally considered to be 5-HT2 agonists, preliminary studies with isolated rat thoracic aorta suggest that some of the more lipophilic derivatives (e.g. the n-hexyl and n-octyl derivatives) are 5-HT2 antagonists.

Journal of Business Finance & AccountingVolume 16, Issue 3 p. 303-315 The Need For Ex Post Eei John R. Grinyer, John R. Grinyer the authors are from the Department of Accountancy and Business Finance at the University of Dundee. They wish to acknowledge financial assistance from the Carnegie Trust for the Universities of Scotland in the development of this paper.Search for more papers by this authorRobert A. Lyon, Robert A. Lyon the authors are from the Department of Accountancy and Business Finance at the University of Dundee. They wish to acknowledge financial assistance from the Carnegie Trust for the Universities of Scotland in the development of this paper.Search for more papers by this author John R. Grinyer, John R. Grinyer the authors are from the Department of Accountancy and Business Finance at the University of Dundee. They wish to acknowledge financial assistance from the Carnegie Trust for the Universities of Scotland in the development of this paper.Search for more papers by this authorRobert A. Lyon, Robert A. Lyon the authors are from the Department of Accountancy and Business Finance at the University of Dundee. They wish to acknowledge financial assistance from the Carnegie Trust for the Universities of Scotland in the development of this paper.Search for more papers by this author First published: June 1989 https://doi.org/10.1111/j.1468-5957.1989.tb00020.xCitations: 8AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat Citing Literature Volume16, Issue3June 1989Pages 303-315 RelatedInformation

It has been shown that the hallucinogenic potencies of LSD, the phenylisopropylamines, such as DOB (4-bromo-2,5-dimethoxyphenylisopropylamine) and DOI (4-iodo-2,5-dimethoxyphenylisopropylamine), and the indoleaklylamines, such as DMT (dimethyltryptamine) and 5-OMe-DMT (5-methoxy-dimethyltryptamine), strongly correlate with their in vitro 5-HT2 receptor binding affinities in rat cortical homogenates. In order to ascertain if this correlation applies to human 5-HT2 receptors as well, we examined the affinities of 13 psychoactive compounds at 3H-ketanserin-labelled 5-HT2 receptors in human cortical samples. Both radioligand binding and autoradiographical procedures were used. As in rat brain d-LSD was the most potent displacer of 3H-ketanserin specific binding with a Ki of 0.9 nM. The phenylisopropylamine DOI also displayed high affinity (Ki of 6 nM). Stereospecific interactions were found with DOB; (-_ DOB had a Ki of 17 nM while (+) DOB had a Ki of 55 nM. The behaviorally active compound DOM (4-methyl-2,5-phenylisopropylamine) had an affinity of 162 nM while its behaviorally less active congener iso-DOM had an affinity of 6299 nM. The indolealkylamines 5-OMe-DMT and DMT competed with moderate affinities (207 and 462 nM, respectively). In general, Hill coefficients were significantly less than unity which is consistent with an agonist interaction with 5-HT2 receptors. MDMA, a substituted amphetamine analog was inactive with a Ki of greater than 10 μM. A strong correlation was found for the hallucinogen affinities and human hallucinogenic potencies (r=0.97). Also, human and rat brain 5-HT2 receptor affinities were strongly correlated (r=0.99). These results strongly support the hypothesis that the hallucinogenic effects of these drugs in humans are mediated in whole or in part via 5-HT2 receptors. Furthermore, these studies imply that treatment with 5-HT2 receptor antagonists may be effective in reversing the hallucinogenic effects caused by the ingestion, of LSD and LSD-like drugs.

The Department of Medicinal Chemistry, together with the Institute for Structural Biology, Drug Discovery and Development, at Virginia Commonwealth University (VCU) has evolved, organically with quite a bit of bootstrapping, into a unique drug discovery ecosystem in response to the environment and culture of the university and the wider research enterprise. Each faculty member that joined the department and/or institute added a layer of expertise, technology and most importantly, innovation, that fertilized numerous collaborations within the University and with outside partners. Despite moderate institutional support with respect to a typical drug discovery enterprise, the VCU drug discovery ecosystem has built and maintained an impressive array of facilities and instrumentation for drug synthesis, drug characterization, biomolecular structural analysis and biophysical analysis, and pharmacological studies. Altogether, this ecosystem has had major impacts on numerous therapeutic areas, such as neurology, psychiatry, drugs of abuse, cancer, sickle cell disease, coagulopathy, inflammation, aging disorders and others. Novel tools and strategies for drug discovery, design and development have been developed at VCU in the last five decades; e.g., fundamental rational structure-activity relationship (SAR)-based drug design, structure-based drug design, orthosteric and allosteric drug design, design of multi-functional agents towards polypharmacy outcomes, principles on designing glycosaminoglycans as drugs, and computational tools and algorithms for quantitative SAR (QSAR) and understanding the roles of water and the hydrophobic effect.

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTIodine-125 labeled 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane: an iodinated radioligand that specifically labels the agonist high-affinity state of 5-HT2 serotonin receptorsRichard A. Glennon, Mark R. Seggel, William H. Soine, Katherine Herrick-Davis, Robert A. Lyon, and Milt TitelerCite this: J. Med. Chem. 1988, 31, 1, 5–7Publication Date (Print):January 1, 1988Publication History Published online1 May 2002Published inissue 1 January 1988https://doi.org/10.1021/jm00396a003RIGHTS & PERMISSIONSArticle Views232Altmetric-Citations85LEARN 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 InReddit PDF (398 KB) Get e-Alertsclose Get e-Alerts

Although simple arylpiperazines are commonly considered to be moderately selective for 5-HT1B serotonin binding sites, N4-substitution of such compounds can enhance their affinity for 5-HT1A sites and/or decrease their affinity for 5-HT1B sites. A small series of 4-substituted 1-arylpiperazines was prepared in an attempt to develop agents with high affinity for 5-HT1A sites. Derivatives where the aryl portion is phenyl, 2-methoxyphenyl, or 1-naphthyl, and the 4-substituent is either a phthalimido or benzamido group at a distance of four methylene units away from the piperazine 4-position, display high affinity for these sites. One of these compounds, 1-(2-methoxyphenyl)-4-[4-(2-phthalimido)butyl]piperazine (18), possesses a higher affinity than 5-HT and represents the highest affinity (Ki = 0.6 nM) agent yet reported for 5-HT1A sites.

8-Hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) is a serotonergic agonist with high affinity and selectivity for a particular population of central serotonin (5-HT) binding sites (i.e., 5-HT,A sites). Because the selectivity of 8-OH-DPAT may be due to the terminal amine substituents, the di-n-propyl analogue of 5-HT (Le., 4) and of 5-methoxytryptamine (Le., 5 ) were prepared and compared with 8-OH-DPAT with respect to their binding profile. Unlike 8-OH-DPAT, neither compound 4 nor 5 displays selectivity for 5-HTIA vs 5-HTz sites. Consistent with these results, stimulus generalization occurs with 5 both in rats trained to discriminate 8-OH-DPAT from saline and in rats trained to discriminate the 5-HTz agonist DOM from saline. The results of this study suggest that it is not the N,N-dipropyl groups that account for selectivity, but, rather, it i s some feature associated with the pyrrole portion of the indolylalkanamines that is important.

1-(4-Bromo-2,5-dimethoxyphenyl)-2-aminopropane (DOB) is a serotonin (5-HT) agonist that displays a high affinity and selectivity for a certain population of central 5-HT binding sites (i.e., 5-HT2 sites). In the present study, (a) an enantiomeric potency comparison was made for the optical isomers of DOB and (b) the activity of N-monomethyl-,N,N-dimethyl-, and N,N,N-trimethyl-DOB was examined. (R)-(-)-DOB (Ki = 0.39 nM) was found to have 6 times greater affinity than its S-(+) enantiomer at [3H]DOB-labeled (rat cortical homogenates) 5-HT2 sites; N-methylation of racemic DOB resulted in a decrease in affinity that was at least 1 order of magnitude per methyl group. Similar results were obtained in an in vivo drug discrimination paradigm with rats as subjects and (R)-(-)-DOB (0.2 mg/kg) as the training drug. Thus, the R-(-) isomer of DOB is more active than its S-(+) enantiomer and than any of the possible N-methyl derivatives of DOB, both with respect to affinity at central 5-HT2 binding sites and with respect to potency in the behavioral (i.e., stimulus generalization) studies.

3,4-Methylenedioxymethamphetamine (MDMA), 3,4-methylenedioxy-amphetamine (MDA), and their optical isomers, were assayed for their affinities at radiolabeled brain serotonin (5-HT1, 5-HT2) and dopamine (D2) binding sites. (R(−)-MDA and R(−)-MDMA) displayed moderate affinities for 3H-ketanserin-labeled 5-HT2 sites (Ki=3425 and 3310 nM, respectively) whereas the affinities for their S(+)-enantiomers were lower (Ki=13,000 and 15,800 nM, respectively). Similar absolute and relative affinities were obtained at 3H-serotonin-labeled 5-HT1 sites; binding at D2 sites was very low (Ki>25,000 nM in each case). The (−)>(+) order of potency at 5-HT2 sites is consistent with the observation that R(−)-MDA is a more potent psychoactive agent than its S(+)-enantiomer, but contrasts with the reported finding that S(+)-MDMA is more potent than R(−)-MDMA in humans. These results suggest that MDMA, unlike MDA and other hallucinogenic phenylisopropylamines, does not work primarily through a direct interaction at 5-HT sites.

The Anatomical RecordVolume 86, Issue 3 p. 417-423 Article Studies on the production of secondary deciduomata during lactation in the rat Robert A. Lyon, Robert A. Lyon Departments of Obstetrics and Gynecology, The University of California Medical School, San Francisco Washington University School of Medicine, St. Louis, MissouriSearch for more papers by this authorWillard M. Allen, Willard M. Allen Departments of Obstetrics and Gynecology, The University of California Medical School, San Francisco Washington University School of Medicine, St. Louis, MissouriSearch for more papers by this author Robert A. Lyon, Robert A. Lyon Departments of Obstetrics and Gynecology, The University of California Medical School, San Francisco Washington University School of Medicine, St. Louis, MissouriSearch for more papers by this authorWillard M. Allen, Willard M. Allen Departments of Obstetrics and Gynecology, The University of California Medical School, San Francisco Washington University School of Medicine, St. Louis, MissouriSearch for more papers by this author First published: July 1943 https://doi.org/10.1002/ar.1090860310Citations: 3AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinkedInRedditWechat Literature Cited Allen, W. M. 1931 I. Cyclical alterations of the endometrium of the rat during the normal cycle, pseudopregnancy and pregnancy. II. Production of deciduomata during pregnancy. Anat. Rec., vol. 48, pp. 65–88. Allen, W. M., and G. P. Heckel 1936 Prolongation of the corpus luteum in the pseudopregnant rabbit. Science, vol. 84, pp. 161–162. Heckel, G. P., and W. M. Allen 1939 Maintenance of the corpus luteum and inhibition of parturition in the rabbit by injection of estrogenic hormone. Endocrinology, vol. 24, pp. 137–148. Krehbiel, R. H. 1941 The effects of lactation on the implantation of ova of a concurrent pregnancy in the rat. Anat. Rec., vol. 81, pp. 43–61. Krehbiel, R. H. 1941 The effects of theelin on delayed implantation in the pregnant rat. Anat. Rec., vol. 81, pp. 381–391. Long, J. A., and H. M. Evans 1922 The oestrous cycle in the rat and its asociated phenomena. Mem. Univ. Calif., vol. 6, p. 1. Lyon, R. A. 1939 Survival of deciduomata during lactation in the rat. Proc. Soc. Exp. Biol. and Med., vol. 40, pp. 151–152. Lyon, R. A., A. W. M., Allen 1938 Duration of sensitivity of the endometrium during lactation in the rat. Am. J. Physiol., vol. 122, pp. 624–626. Selye, H., and T. McKeown 1935 Studies on the physiology of the maternal placenta in the rat. Proc. Roy. Soc. London, series B, vol. 119, pp 1–31. Welchert, C. K. 1940 The experimental shortening of delayed pregnancy in the albino rat. Anat. Rec., vol. 77, pp. 31–43. Welchert, C. K. 1942 The experimental control of prolonged pregnancy in the lactating rat by means of estrogen. Anat. Rec., vol. 83, pp. 1–14. Citing Literature Volume86, Issue3July 1943Pages 417-423 ReferencesRelatedInformation

ArticleDURATION OF SENSITIVITY OF THE ENDOMETRIUM DURING LACTATION IN THE RATRobert A. Lyon, and Willard M. AllenRobert A. LyonFrom the Departments of Anatomy, and Obstetrics and Gynecology, University of Rochester, School of Medicine and Dentistry, and Willard M. AllenFrom the Departments of Anatomy, and Obstetrics and Gynecology, University of Rochester, School of Medicine and DentistryPublished Online:31 May 1938https://doi.org/10.1152/ajplegacy.1938.122.3.624MoreSectionsPDF (390 KB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations ShareShare onFacebookTwitterLinkedInWeChat Previous Back to Top Next Download PDF FiguresReferencesRelatedInformation More from this issue > Volume 122Issue 3May 1938Pages 624-626 Copyright & PermissionsCopyright © 1938 by American Physiological Societyhttps://doi.org/10.1152/ajplegacy.1938.122.3.624History Received 11 February 1938 Published online 31 May 1938 Published in print 31 May 1938 Metrics

The Anatomical RecordVolume 65, Issue 3 p. 351-356 Article Survival of deciduomata in the unilaterally pregnant rat Robert A. Lyon, Robert A. Lyon Department of Obstetrics and Gynecology, University of Rochester, School of Medicine and DentistrySearch for more papers by this authorWillard M. Allen, Willard M. Allen Department of Obstetrics and Gynecology, University of Rochester, School of Medicine and DentistrySearch for more papers by this author Robert A. Lyon, Robert A. Lyon Department of Obstetrics and Gynecology, University of Rochester, School of Medicine and DentistrySearch for more papers by this authorWillard M. Allen, Willard M. Allen Department of Obstetrics and Gynecology, University of Rochester, School of Medicine and DentistrySearch for more papers by this author First published: June 1936 https://doi.org/10.1002/ar.1090650308Citations: 2AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat Citing Literature Volume65, Issue3June 1936Pages 351-356 RelatedInformation