DETAILED DESCRIPTION The present invention pertains to novel TRH analogues, compositions, and methods for the controlled administration of novel TRH analogues to mammals.
The present invention preferably provides centrally active TRH analogues that are metabolically stable, provide enhanced CNS-targeting, and when therapeutically administered, do not manifest unwanted endocrine effect while still providing therapeutically active compounds.
In one aspect of the invention, TRH analogues of the present invention are used for treating diverse physical and neurological conditions such as fatigue, depression, schizophrenia, circulatory shock, amyotrophic lateral sclerosis, spinal cord injury and hypertension.
In a further aspect, TRH analogues of the present invention are administered to treat central nervous system disorders such as Alzheimer's disease, brain or spinal cord trauma, and motorneuron disease.
The present invention provides centrally active TRH analogues in which either the histidyl portion, the N-terminal/pyroglutamyl portion, or the C-terminal amide portion of TRH is substituted with pyridinium derivatives.
The present invention further includes centrally active TRH analogues in which additional substitutions (i.
e.
, at the histidyl portion) are presented to form negative ions.
In an embodiment, as exemplified herein, TRH analogues are provided in which the histidyl portion of TRH is substituted with a pyridinium derivative.
In another embodiment, as exemplified herein, TRH analogues are provided in which the histidyl portion of TRH is substituted with a linker group and carboxyl moiety, sulphonate, or phosphonate.
Another embodiment provides TRH analogues in which the N-terminal, pyroglutamyl portion of TRH is modified with pyridinium derivatives.
In yet another embodiment, the C-terminal amide of TRH is substituted with pyridinium derivatives to form a quaternary pyridinium compound.
The pyridinium derivative substitutions of the present invention advantageously provide a permanent positive charge to the TRH analogues of the subject invention to enable enhanced nervous system activity, prevent enzymatic degradation, and connote metabolic stability
|
Gene Therapy 
