Novel non-indolic melatonin receptor agonists differentially entrain endogenous melatonin rhythm and increase its amplitude.
In this study we have examined the ability of melatonin and four synthetic melatonin receptor agonists to entrain endogenous melatonin secretion in rats, free running in constant darkness. The circadian melatonin profile was measured by trans-pineal microdialysis, which not only reveals the time of onset and end of production (phase), but also the amplitude of the rhythm. Exogenous melatonin given at the onset of subjective darkness (clock time 12 h) was effective to entrain endogenous melatonin production. Only one agonist, 2-chloroacetamido-8-methoxytetralin (AH-017), mimicked this action. Two other agonists, 4-methoxy-2-(methylene propylamide)indan (GG-012) and N-[2-[2,3,7,8-tetrahydro-1H-furo(2, 3-g)indol-1-yl]ethyl]acetamide (GR196429), induced a phase-delay under free running conditions, possibly by increasing tau (tau) period. One agonist, 2-acetamido-8-methoxytetralin (AH-001) did not show any phase effect on the free running rhythm. Unexpectedly, all melatonin receptor agonists increased the amplitude of melatonin secretion. The amount of the increase varied from just below the level of significance (AH-001) to an approximately 2-fold increase (GG-012 and GR196429). This is in clear contrast to entrainment with melatonin, which significantly decreased the amplitude. It is hypothesized that entrainment and effects on amplitude of melatonin secretion are mediated by different mechanisms which can be differentially modulated using specific ligands.
Drijfhout
W J
WJ
University Centre for Pharmacy, Department of Medicinal Chemistry, University of Groningen, A. Deusinglaan 1, 9713 AV, Groningen, Netherlands.
de Vries
J B
JB
Homan
E J
EJ
Brons
H F
HF
Copinga
S
S
Gruppen
G
G
Beresford
I J
IJ
Hagan
R M
RM
Grol
C J
CJ
Westerink
B H
BH
D000818:Animals; D002851:Chromatography, High Pressure Liquid; D002940:Circadian Rhythm; D007189:Indans / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D008297:Male; D008550:Melatonin / Q000378:metabolism* / Q000494:pharmacology; D017551:Microdialysis; D010870:Pineal Gland / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D011956:Receptors, Cell Surface / Q000819:agonists*; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists*; D044094:Receptors, Melatonin; D013764:Tetrahydronaphthalenes / Q000494:pharmacology; D013997:Time Factors
C402299:2-chloroacetamido-8-methoxytetralin; C402300:4-methoxy-2-(methylene propylamide)indan; C112779:GR 196429; D007189:Indans; D007211:Indoles; D011956:Receptors, Cell Surface; D018160:Receptors, Cytoplasmic and Nuclear; D044094:Receptors, Melatonin; D013764:Tetrahydronaphthalenes; C083680:AH 001; D008550:Melatonin