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The analogues were evaluated as agonists at TRH\u2010R1 and TRH\u2010R2 in cells in\u2005vitro, and in\u2005vivo in mice for analeptic and anticonvulsant activities. Several analogues bound to TRH\u2010R1 and TRH\u2010R2 with good to moderate affinities, and are full agonists at both receptor subtypes. Specifically, analogue <jats:bold>21\u2009a<\/jats:bold> (R=CH<jats:sub>3<\/jats:sub>) exhibited binding affinities (<jats:italic>K<\/jats:italic><jats:sub>i<\/jats:sub> values) of 0.17\u2005\u03bc<jats:sc>M<\/jats:sc> for TRH\u2010R1 and 0.016\u2005\u03bc<jats:sc>M<\/jats:sc> for TRH\u2010R2; it is 10\u2010fold less potent than TRH in binding to TRH\u2010R1 and equipotent with TRH in binding to TRH\u2010R2. Compound <jats:bold>21\u2009a<\/jats:bold>, the most selective agonist, activated TRH\u2010R2 with a potency (EC<jats:sub>50<\/jats:sub> value) of 0.0021\u2005\u03bc<jats:sc>M<\/jats:sc>, but activated TRH\u2010R1 at EC<jats:sub>50<\/jats:sub>=0.05\u2005\u03bc<jats:sc>M<\/jats:sc>, and exhibited 24\u2010fold selectivity for TRH\u2010R2 over TRH\u2010R1. The newly synthesized TRH analogues were also evaluated in\u2005vivo to assess their potencies in antagonism of barbiturate\u2010induced sleeping time, and several analogues displayed potent analeptic activity. Specifically, analogues <jats:bold>21\u2009a<\/jats:bold>,<jats:bold>b<\/jats:bold> and <jats:bold>22\u2009a<\/jats:bold>,<jats:bold>b<\/jats:bold> decreased sleeping time by nearly 50\u2009% more than TRH. These analogues also displayed potent anticonvulsant activity and provided significant protection against PTZ\u2010induced seizures, but failed to provide any protection in MES\u2010induced seizures at 10\u2005\u03bcmol\u2009kg<jats:sup>\u22121<\/jats:sup>. The results of this study provide evidence that TRH analogues that show selectivity for TRH\u2010R2 over TRH\u2010R1 possess potent CNS activity.<\/jats:p>","DOI":"10.1002\/cmdc.201000481","type":"journal-article","created":{"date-parts":[[2011,2,7]],"date-time":"2011-02-07T12:12:23Z","timestamp":1297080743000},"page":"531-543","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Synthesis, Receptor Binding, and CNS Pharmacological Studies of New Thyrotropin\u2010Releasing Hormone (TRH) Analogues"],"prefix":"10.1002","volume":"6","author":[{"given":"Vikramdeep","family":"Monga","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chhuttan L.","family":"Meena","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Satyendra","family":"Rajput","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chandrashekhar","family":"Pawar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shyam S.","family":"Sharma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinping","family":"Lu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marvin C.","family":"Gershengorn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rahul","family":"Jain","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2011,2,7]]},"reference":[{"key":"e_1_2_6_1_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.pa.26.040186.001523"},{"key":"e_1_2_6_2_2","doi-asserted-by":"publisher","DOI":"10.1210\/er.20.5.599"},{"key":"e_1_2_6_3_2","first-page":"1870","volume":"269","author":"Burgus R.","year":"1969","journal-title":"C. 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