Title:  Mediation of circadian rhythms

United States Patent:  6,403,651

Assignee:  Luminis Pty Limited (South Australia, AU)

Filed:  March 6, 2000

PCT NO:  PCT/AU98/00207

102(e) Date:  March 6, 2000

PCT PUB. Date:  October 1, 1998

Foreign Application Priority Data:  Mar 26, 1997[AU] (P0 5882)

Method for mediating the effects of light on melatonin rhythmicity in mammals and a method of mediating circadian rhythms, effected by the administration of a compound or compounds effective at a 5-HT2c serotonin receptor site. By administration of selected doses of the 5-HT2c receptor active compound it is possible to advance or delay circadian rhythms as measured by the rate of melatonin production or moderation of core body temperature rhythms.

SUMMARY OF THE INVENTION

Therefore, according to one aspect of the present invention, there is provided a method of mediating the effects of light on melatonin rhythmicity or mediating the effects of cicadian rhythms in mammals in need of such treatment comprising administering a therapeutically effective amount of a compound, or compounds, having a high affinity for a serotonin 5-HT2c receptor.

Advantageously, the timing of administration of the compound can be predetermined to coincide with an appropriate phase on an existing circadian rhythm to produce a selected mediation of the cycle.

It has been found that the administration of compounds having a high affinity for the serotonin 5-HT2c receptor site are able to phase shift an existing circadian rhythm by inhibiting melatonin production and causing delays in the onset of melatonin production for up to 3 nights following administration. In addition, it is known that core body temperature follows a circadian rhythm which can also be mediated by the administration of compounds, having a high affinity for a serotonin 5-HT2c receptor.

Among the compound or compounds having a high affinity for the 5-HT2c serotonin receptor are the following, although it should be stressed that the invention is not limited to these compounds:

(+/-)-1-(4-iodo-2,5-dimethoxy-phenyl)-2-aminopropane, (DOI); 1-(3-chlorophenyl)piperazine, (mCPP) and compounds which are metabolised to mCPP (desyrel, nefazodone and tradozone); 1-(.alpha.,.alpha.,.alpha.-trifluoro-m-tolyl)-piperazine, (TFMPP); (dl)-4-bromo-2,5-dimethoxyamphetamineHCl, (DOB); (dl)-2,5-dimethoxy-4-methylamphetamine HCl, (DOM); mesulergine; ritanserin; (clozapine; loxapine; R(+)-2-di-n-propylamino-8-hydroxy-1,2,3,4-tetrahydronapthalene, (SCH 23390); tiosperone; fluperlapine; rilapine; chlorpromazine; ketanserin; risperidone; cis-fluphenixol; quipazine; 6-chloro-2-(1-piperazinyl)pyrazine, (MK-212); spiperone; metergoline; methysergide; 6-methyl-1-(1-methylethyl)-ergoline-8-carboxylic acid (8.beta.)-2-hydroxy-1-methylpropyl ester(Z)-2-butenedioate(1:1), (LY-53857); methiothepin; cyproheptadine; perenpirone; N-(1-methyl-5-indolyl-N-(3-pyridyl) urea, (SB-200646); pitozifen; 2-(2-dimethylaminoethylthio)-3-phenylquinoline, (ICI-169-369); lisuride; methergine; piremperone; ergometrine.

Preferably, the serotonin 5-HT2c receptor active compound is selected from the, group consisting of: DOI, mCPP, TFMPP, MK-212, and quipazine. More preferably still, the serotonin 5-HT2c receptor active compound is DOI.

Preferably, the serotonin 5-HT2c receptor active compound is administered at a concentration of 0.005-25 mg/kg of body weight.

In further aspects of the present invention it is possible to administer the therapeutically effective amount of a serotonin 5-HT2c receptor active compound or compounds in a timed manner, optionally in combination with melatonin to thereby further mediate an existing circadian rhythm, and in one form the invention may comprise a pharmaceutical package containing one or more therapeutically effective doses of a serotonin 5-HT2c receptor active compound or compounds, the package containing suitable indicia for calculating the dosage and timing of administration of the dosage to produce a selected mediation of the melatonin production cycle. The invention further comprises a method of treatment of the following conditions in mammals by administration of a therapeutically effective amount of a serotonin 5-HT2c receptor active compound; advanced phase sleep insomnia, delayed sleep phase insomnia, Seasonal Affective Disorder, Shift Work dysrhythmia, jet-lag, and the control of physiological systems which respond to light, and the control of seasonal breeding cycles of animals. Typically, the mediating effect on the circadian rhythms can be monitored experimentally in rats from an analysis of the output of the pineal gland via the urinary metabolite of melatonin, 6-sulphatoxymelatonin (aMT.6S) following drug treatment to provide information on the transmitters mediating the effects of light. Experimentally rats are maintained in metabolism cages and fed a high protein liquid diet to promote urine flow during the night. Urine produced is continuously pumped out of the urine collection vessels by a peristaltic pump and deposited in vials in a multi-channel fraction collector. Using this arrangement, hourly samples can be obtained non-invasively for more than four days. It can be demonstrated that light presented between 2-8 hours after dark onset (ie between ZT14 and ZT20) results in the acute suppression of aMT.6S excretion and causes the normal nocturnal increase to be delayed by several hours on subsequent nights. In subsequent studies, it has been found that light pulses of low intensity (2 lux) and short duration (1 minute) have this dual effect of acute suppression and phase delay when presented at CT18, that is 6 hours after subjective lights out in animals maintained in continuous darkness. The effects of administering an appropriate dose of an agonist compound having a high affinity for a serotonin 5-HT2c receptor provokes the equivalent of these light effects on pineal rhythmicity and causes a dose dependent acute suppression in melatonin production and a delay of up to several hours in the on set of production in subsequent nights. Thus, an existing circadian rhythm is delayed by the administration of the compounds to the extent of the delay in on set of production of melatonin. Alternatively, administration of a serotonin antagonist having a high affinity for the 5-HT2c receptor would block the phase advancing or delaying effects of a light pulse on the melatonin rhythm.

Additionally, by administering a plurality of doses of an appropriate 5-HT2c receptor active compound, or mixture of compounds at intervals, it is possible to induce a phase advance of a circadian rhythm. Thus, by administering repetitive doses, for example on two or more successive days just before subjective dawn (ie in the hours ZT21-ZT24) it will be possible to produce a phase advance of several hours. The administration of doses can be maintained until the desired mediated rhythm is established.

Claim 1 of 12 Claims

I claim:

1. A method of mediating the effects of circadian rhythms in mammals comprising the step of administering a therapeutically effective amount of at least one compound having a high affinity and selectivity for a serotonin 5-HT_2c receptor.

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