the present invention comprises a series of compounds and their use in the treatment of neurologic disorders . the compounds are novel thyrotropin - releasing hormone analogs which are preferably used in the treatment of brain and spinal cord trauma . the injury is treated by administering an effective amount of a compound to the patient wherein the compound preferably reduces the secondary effects of the trauma by optimally antagonizing the actions of autodestructive biochemical substances , such as endogenous opioids , without being rapidly metabolized . preferably , the compound penetrates the central nervous system . in a first preferred embodiment of the present invention , the compound is a trh analog having the following structure : ## str3 ## wherein r or r &# 39 ; or both are halogens such as r ═ i and r &# 39 ;═ i or r ═ f and r &# 39 ;═ h , or r ═ i and r &# 39 ;═ h , or r ═ br and r &# 39 ;═ br , or r ═ br and r &# 39 ;═ h . alternatively , r ═ cf 3 and r &# 39 ;═ h or the r and r &# 39 ; are reversed so that r ═ h and r &# 39 ;═ cf 3 . in another alternative , r ═ no 2 and r &# 39 ;═ h . in a second preferred embodiment of the present invention , the compound is a trh analog having the following structure : ## str4 ## wherein r ═ no 2 and r &# 39 ;═ h . alternatively , r ═ cf 3 and r &# 39 ;═ h or the r and r &# 39 ; are reversed so that r ═ h and r &# 39 ;═ cf 3 . in another alternative , r or r &# 39 ; or both are halogens such as r ═ f and r &# 39 ;═ h , or r ═ i and r &# 39 ;═ i , or r ═ i and r &# 39 ;═ h , or r ═ br and r &# 39 ;═ br , or r ═ br and r &# 39 ;═ h . in a third preferred embodiment of the present invention , the compound is a trh analog having the following structure : ## str5 ## wherein r ═ cf 3 and r &# 39 ;═ h . alternatively , the r and r &# 39 ; are reversed so that r ═ h and r &# 39 ;═ cf 3 . in another alternative , r ═ no 2 and r &# 39 ;═ h . in yet another alternative , r or r &# 39 ; or both are halogens such as r ═ f and r &# 39 ;═ h , or r ═ i and r &# 39 ;═ i , or r ═ i and r &# 39 ;═ h , or r ═ br and r &# 39 ;═ br , or r ═ br and r &# 39 ;═ h . in a fourth preferred embodiment of the present invention , the compound is a trh analog having the following structure : ## str6 ## wherein r ═ cf 3 and r &# 39 ;═ h . alternatively , the r and r &# 39 ; are reversed so that r ═ h and r &# 39 ;═ cf 3 . in another alternative , r ═ no 2 and r &# 39 ;═ h . in yet another alternative , r or r &# 39 ; or both are halogens such as r ═ f and r &# 39 ;═ h , or r ═ i and r &# 39 ;═ i , or r ═ i and r &# 39 ;═ h , or r ═ br and r &# 39 ;═ br , or r ═ br and r &# 39 ;═ h . in a fifth preferred embodiment of the present invention , the compound is a trh analog having the following structure : ## str7 ## wherein r ═ cf 3 and r &# 39 ;═ h . alteratively , the r and r &# 39 ; are reversed so that r ═ h and r &# 39 ;═ cf 3 . in another alternative , r ═ no 2 and r &# 39 ;═ h . in yet another alternative , r or r &# 39 ; or both are halogens such as r ═ f and r &# 39 ;═ h , or r ═ i and r &# 39 ;═ i , or r ═ i and r &# 39 ;═ h , or r ═ br and r &# 39 ;═ br , or r ═ br and r &# 39 ;═ h . the first preferred novel trh analog of the present invention is synthesized by starting with the compound n - ( 5 )- 4 - oxo - 2 - azetidinyl ! carbonyl !- l - histadyl - l - prolineamide dihydrate known in the industry as ym - 14673 , which is available through yamanouchi pharmaceutical co . ltd ( tokyo , japan ). the various substitutions are created in accordance with the method of labroo , v . m ., feurerstein , g ., and cohen , l . a ., in &# 34 ; peptides : structure and function &# 34 ; proceedings of the ninth american peptide symposium , deber , hruby and kopple , eds ., pp . 703 - 706 , 1985 , which is incorporated herein by reference . the second preferred novel trh analog is synthesized by starting with the compound orotyl - l - histidyl - l - prolineamide , known in the industry as cg 3703 , which is available through chemie grunenethal ( stolberg , west germany ). the various substitutions are created in accordance with the method of labroo cited above . the third preferred novel trh analog of the present invention is synthesized by starting with the thryotropin releasing hormone and modifying it in accordance with method known to those skilled in the art . the various substitutions are created in accordance with the method of labroo cited above . the fourth preferred novel trh analog of the present invention is synthesized by starting with the compound known in the industry as cg 3509 , which is available through chemie grunenethal ( stolberg , west germany ). the various substitutions are created in accordance with the method of labroo cited above . the fifth preferred novel trh analog of the present invention is synthesized by starting with the compound γ - butyrolactone - γ - carbonyl - l - histidyl - l - proline amide citrate , known in the industry as dn 1417 , which is available through takeda chemical industries , ltd . ( osaka , japan ). the various substitutions are created in accordance with the method of labroo cited above . an effective dose of the trh analog of the present invention comprises an amount of the analog sufficient to reduce secondary injury by blocking or reducing the release of injurious endogenous substances . preferably , the effective dose is from approximately 0 . 1 to 10 . 0 mg / kg body weight of the patient . this dose is preferably administered every 4 - 6 hours for approximately 24 hours to treat trauma . it will be understood by those skilled in the art that the compound is administered chronically for the treatment of other neurologic disorders such as stroke ; systic , hypovolemic or anaphylactic shock ; neurodegenerative disorders such as amyotropic lateral sclerosis or spinocerebellar degeneration ; and unconsciousness or subconsciousness due to anesthetics or overdoses . most preferably the effective dose of the trh analog of the present invention is approximately 1 . 0 mg / kg body weight of the patient administered every 4 - 6 hours within the first 24 hours after trauma . although not wanting to be bound by the following hypothesis , it is believed that the preferred embodiments of the trh analog of the present invention increase neurologic recovery by blocking the actions of several injury factors including opioids , leukotrienes , and platelet activating factor released as a consequence of the trauma . the analog may also inhibit lipid membrane breakdown , i . e . reduce the release of polyunsaturated fatty acids and eicosanoids which are toxic to central nervous system tissue . the trh analog may also act by maintaining magnesium homeostasis . furthermore , halogenation of the histidyl portion of the analog may enhance blood - brain barrier penetration . the therapeutic route of administration of the compound of the present invention includes , but is not limited to , intravenous , intramuscular , subcutaneous , and oral administration . preferably , the compound is administered intravenously . the compound of the present invention can be administered as a liquid or gel by any of the above described routes of administration or orally in the form of a solid tablet . preferably , the compound is administered to the patient in the form of a liquid solution , the solution comprising an effective amount of active ingredient compound and a pharmaceutically acceptable solution . the pharmaceutically acceptable solution includes any solution that is safe for injection or ingestion and is biologically inert so that it does not interfere with the active ingredient . the preferred pharmaceutically acceptable solution comprises an isotonic solution suitable for injection into a patient . for example , the isotonic solution may contain water , salt , and conventional ingredients such as glucose . the pharmaceutically acceptable solution may also contain purified water mixed with preservatives , flavors , colorants , flavor enhancing agents , and other additives such as sodium benzoate , methyl paraben , propylene glycol , glycerin , sorbitol , alcohol , sucrose , saccharin , menthol and citric acid . as described above , the trh analog of the present invention is preferably used to treat brain and spinal cord injuries caused by central nervous system trauma . however , the trh analog of the present invention can also be administered to a patient undergoing a tissue transplant by reducing secondary traumatic injury associated with the transplant process . the following specific examples will illustrate the invention as it applies in particular to improving neurologic function . it will be appreciated that other examples will be apparent to those of ordinary skill in the art and that the invention is not limited to these specific illustrative examples . an experiment is described to illustrate the effect of the following trh analog on neurological function : ## str8 ## wherein r and r &# 39 ;═ i . following anesthesia with pentobarbital ( 60 mg / kg , i . p .) male , sprague - dawley rats ( 400 ± 25 g ) are subjected to traumatic brain injury utilizing a lateral , fluid - percussion . the fluid - percussion device used to produce experimental brain injury is a plexiglas cylindrical reservoir , 60 cm long and 4 . 5 cm in diameter , bounded at one end by a plexiglas , cork - covered piston mounted on o rings . the opposite end of the reservoir is fitted with a 2 - cm - long metal housing on which a transducer ( gould ) is mounted and connected to a 5 - mm tube ( 2 mm id ) that terminates with a male luer lok fitting . at the time of injury , the tube is connected to a female luer lok fitting that has been chronically implanted over the exposed cortex of the rat . after the entire system is filled with 37 ° c . isotonic saline , injury is induced by a metal pendulum , which strikes the piston of the device from a predetermined height . the device produces a pulse of increased intracranial pressure of fairly constant duration ( 21 - 23 ms ) by injecting varying volumes of saline into the closed cranial cavity . brief displacement and deformation of neural tissue results from the rapid epidural injection of saline , and increased magnitude of tissue deformation is associated with an increased magnitude of brain injury . the magnitude of injury is regulated by varying the height of the pendulum , which results in corresponding variations in intracranial pressure pulses expressed in atmospheres . these pressure pulses are measured extracranially by a transducer ( housed in the injury device ) at the time of injury , recorded on a storage oscilloscope , and photographed with a polaroid camera . male , sprague - dawley rats ( 300 ± 25 g are anesthetized with sodium pentobarbital ( 60 mg / kg , i . p .) and laminectomy is performed at t 9 . the spinal cord is injured using a modification of the weight - drop method in which a 10 g weight is dropped a distance of 5 cm through a guide tube onto a teflon impounder plate that strikes the exposed spinal cord . this 50 g - cm impact force causes severe , reproducible , but incomplete tissue injury ( control animals show moderately severe spastic paraparesis 4 weeks after trauma ). a catheter is inserted into the jugular vein for drug administration . at 30 min following a 2 . 5 atmosphere level injury , animals are randomly assigned to one of two treatment groups ( each n = 8 ): the above - described trh analog ( 1 . 0 mg / kg ) or equal volume ( 1 cc ) physiological saline , each administered as a slow intravenous bolus injection over 60 sec . at 15 min following spinal cord trauma , animals are randomly assigned to one of two treatment groups : the above - described trh analog ( n = 17 ) or equal volume ( 1 cc ) physiological saline ( n = 15 ), each administered as a slow intravenous bolus injection over 60 sec . neurological function is evaluated daily over a 2 - week period by an individual unaware of treatment group . animals are evaluated separately for five tests of motor function , each scored on an ordinal scale from 0 ( severely impaired ) to 4 ( normal function ). tests include : ( a ) ability to maintain position on an inclined plane in either the vertical or horizontal position for 5 sec ; ( b ) forelimb flexion following suspension by the tail ; ( c ) the degree of resistance to lateral pulsion ; and ( d ) activity monitored in a computerized opto - varimex activity chamber ( columbus instruments ). each of the five individual scores -- vertical angle , horizontal angle , forelimb flexion , lateral pulsion , and activity -- are added to yield a composite neurological score that ranges from 0 to 20 . animals are maintained for 2 weeks . animals are scored blindly over a 4 - week period after trauma utilizing an 8 - point ordinal scale based on motor function : 0 = no spontaneous movements ; 1 = spontaneous movements but unable to support weight ; 2 = supports weight only briefly ; 3 = stands , but unable to walk ; 4 = walks , but with severe spasticity and ataxia ; 5 = walks , but with moderate marked spasticity ; 6 = walks with minimal spasticity ; 7 = normal motor function . animals are also graded as either walkers ( score = 4 - 7 ) or nonwalkers ( score = 0 - 3 ). in addition , rats are scored on their ability to maintain themselves on an inclined plane in the vertical and horizontal positions for 5 sec , with the maximal angle noted . composite neurological scores at 2 weeks after traumatic brain injury are significantly higher in the treatment group animals than in controls . trh analog treatment also improves neurological outcome at 4 weeks after traumatic spinal cord injury . the present study shows that the above - described trh analog , administered as a single bolus intravenous injection after trauma , significantly improves neurological outcome following fluid - percussion - induced lateral brain injury and impact spinal cord trauma in rats . it should be understood , of course , that the foregoing relates only to preferred embodiments of the present invention and that numerous modifications or alterations may be made therein without departing from the spirit and the scope of the invention as set forth in the appended claims .
a series of novel thyrotropin - releasing hormone analogs wherein the c - terminal prolineamide moiety has been preserved , the n - terminal moiety comprises one of five different ring structures and the histidyl moiety is substituted with cf 3 , no 2 or a halogen . a method of use of the analog for the treatment of neurologic disorders is also provided .