Linked Life Data

21368006

Source:http://linkedlifedata.com/resource/pubmed/id/21368006

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
3
pubmed:dateCreated
2011-5-17
pubmed:abstractText
Melatonin, the MT(2) melatonin receptor agonist IIK7 [N-butanoyl-2-(2-methoxy-6H-isoindolo[2,1-a]indol-11-yl)ethanamine], and the putative MT(3) melatonin receptor agonist 5-MCA-NAT [5-methoxycarbonylamino-N-acetyltryptamine] have previously been shown to reduce intraocular pressure (IOP) in ocular normotensive rabbits. To gain a better understanding of the structure-activity relationship of compounds that activate MT(2) and MT(3) receptors mediating reductions in IOP, novel melatonin analogs with rationally varied substitutions were synthesized and tested for their effects on IOP in ocular normotensive rabbits (n = 160). All synthesized melatonin analogs reduced IOP. The best-effect lowering IOP was obtained with the analogs INS48848 [methyl-1-methylene-2,3,4,9-tetrahydro-1H-carbazol-6-ylcarbamate], INS48862 [methyl-2-bromo-3-(2-ethanamidoethyl)-1H-indol-5-ylcarbamate], and INS48852 [(E)-N-(2-(5-methoxy-1H-indol-3-yl)ethyl)-3-phenylprop-2-enamide]. These compounds produced dose-dependent decreases in IOP that were maximal at 0.1 mM (total dose of 0.259 ?g for INS48848, 0.354 ?g for INS48862, and 0.320 ?g for INS48852) and 1 mM (total dose of 2.59 ?g for INS48848, 3.54 ?g for INS48862, and 3.20 ?g for INS48852), with maximal reductions of 36.0 ± 4.0, 24.0 ± 1.5, and 30.0 ± 1.5% for INS48848, INS48862, and INS48852, respectively. Studies using melatonin receptor antagonists (luzindole, prazosin, and DH97 [N-pentanoyl-2-benzyltryptamine]) indicated that INS48862 and INS48852 activate preferentially a MT(2) melatonin receptor and suggest that INS48848 may act mainly via a MT(3) receptor. The most effective compounds were also well tolerated in a battery of standard ocular surface irritation studies. The implication of these findings to the design of novel drugs to treat ocular hypertension is discussed.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Jun
pubmed:issn
1521-0103
pubmed:author
pubmed:issnType
Electronic
pubmed:volume
337
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
703-9
pubmed:meshHeading
pubmed:year
2011
pubmed:articleTitle
Design of novel melatonin analogs for the reduction of intraocular pressure in normotensive rabbits.
pubmed:affiliation
Departamento Bioquímica, Escuela Universitaria de Óptica, Universidad Complutense Madrid, C/Arcos de Jalón 118, 28037 Madrid, Spain.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't