Differential inverse agonist efficacies of SB-258719, SB-258741 and SB-269970 at human recombinant serotonin 5-HT7 receptors.

@article{citeulike:714137, abstract = {Recombinant 5-hydroxytryptamine 5-HT7 receptors are known to express constitutive, i.e., agonist-independent activity. Nonselective ligands, like methiothepin, ritanserin or clozapine behave as full inverse agonists at 5-HT7 receptors. The aim of the present study was to evaluate the degree of inverse agonist activity of three selective 5-HT7 receptor antagonists ((R)-3,N-dimethyl-N-[1-methyl-3-(4-methyl-piperidin-1-yl)propyl]benzene sulfonamide or SB-258719, R-(+)-1-(toluene-3-sulfonyl)-2-[2-(4-methylpiperidin-1-yl)ethyl]-pyrrolidine or SB-258741 and (R)-3-(2-(2-(4-methylpiperidin-1-yl)ethyl)-pyrrolidine-1-sulfonyl)-phenol or SB-269970) in the same model. cAMP accumulation was measured in intact Chinese hamster ovary (CHO) cells expressing human recombinant 5-HT7a receptors. In these cells, 5-HT stimulated cAMP levels and a series of ligands antagonized the effect of 5-HT with a 5-HT7 receptor-like profile. SB-258719 had no inverse agonist activity, SB-258741 behaved as a partial inverse agonist and SB-269970 was a quasi-full inverse agonist (as compared to methiothepin). The inverse agonist effect of SB-269970 was antagonized in a concentration-dependent manner by SB-258719. The widespread spectrum of inverse agonist activities shown by these compounds should help assessing the physiological relevance of constitutive 5-HT7 receptor activity in native tissues.}, address = {Neuroscience Research, Novartis Institutes for Biomedical Research, Novartis Pharma AG, WSJ-386.7.44, CH-4002 Basel, Switzerland.}, author = {Mah\'{e}, C. and Loetscher, E. and Feuerbach, D. and M\"{u}ller, W. and Seiler, M. P. and Schoeffter, P. }, citeulike-article-id = {714137}, doi = {10.1016/j.ejphar.2004.05.033}, issn = {0014-2999}, journal = {Eur J Pharmacol}, keywords = {5-ht7, 5-ht7antagonist, sb-258719, sb-269970}, month = {July}, number = {2-3}, pages = {97--102}, posted-at = {2006-06-28 17:42:01}, priority = {2}, title = {Differential inverse agonist efficacies of SB-258719, SB-258741 and SB-269970 at human recombinant serotonin 5-HT7 receptors.}, url = {http://dx.doi.org/10.1016/j.ejphar.2004.05.033}, volume = {495}, year = {2004} }

TY - JOUR ID - citeulike:714137 L3 - citeulike-article-id:714137 TI - Differential inverse agonist efficacies of SB-258719, SB-258741 and SB-269970 at human recombinant serotonin 5-HT7 receptors. JF - Eur J Pharmacol VL - 495 IS - 2-3 SP - 97 EP - 102 AD - Neuroscience Research, Novartis Institutes for Biomedical Research, Novartis Pharma AG, WSJ-386.7.44, CH-4002 Basel, Switzerland. SN - 0014-2999 N2 - Recombinant 5-hydroxytryptamine 5-HT7 receptors are known to express constitutive, i.e., agonist-independent activity. Nonselective ligands, like methiothepin, ritanserin or clozapine behave as full inverse agonists at 5-HT7 receptors. The aim of the present study was to evaluate the degree of inverse agonist activity of three selective 5-HT7 receptor antagonists ((R)-3,N-dimethyl-N-[1-methyl-3-(4-methyl-piperidin-1-yl)propyl]benzene sulfonamide or SB-258719, R-(+)-1-(toluene-3-sulfonyl)-2-[2-(4-methylpiperidin-1-yl)ethyl]-pyrrolidine or SB-258741 and (R)-3-(2-(2-(4-methylpiperidin-1-yl)ethyl)-pyrrolidine-1-sulfonyl)-phenol or SB-269970) in the same model. cAMP accumulation was measured in intact Chinese hamster ovary (CHO) cells expressing human recombinant 5-HT7a receptors. In these cells, 5-HT stimulated cAMP levels and a series of ligands antagonized the effect of 5-HT with a 5-HT7 receptor-like profile. SB-258719 had no inverse agonist activity, SB-258741 behaved as a partial inverse agonist and SB-269970 was a quasi-full inverse agonist (as compared to methiothepin). The inverse agonist effect of SB-269970 was antagonized in a concentration-dependent manner by SB-258719. The widespread spectrum of inverse agonist activities shown by these compounds should help assessing the physiological relevance of constitutive 5-HT7 receptor activity in native tissues. KW - 5-ht7 KW - 5-ht7antagonist KW - sb-258719 KW - sb-269970 AU - Mahé, C AU - Loetscher, E AU - Feuerbach, D AU - Müller, W AU - Seiler, MP AU - Schoeffter, P PY - 2004/07/14/ UR - http://dx.doi.org/10.1016/j.ejphar.2004.05.033 ER -