Conantokins

#The invention relates to relatively short peptides (termed conantokins herein), about 10-30 residues in length, which are naturally available in minute amounts in the venom of the cone snails or analogous to the naturally available peptides, and which include preferably one to two or more γ-carboxyglutamic acid residues. The conantokins are useful for the treatment of neurologic and psychiatric disorders, such as anticonvulsant agents, as neuroprotective agents or for the management of pain.

#The publications and other materials used herein to illuminate the background of the invention, and in particular, cases to provide additional details respecting the practice, are incorporated by reference, and for convenience are referenced in the following text by author and date and are listed alphabetically by author in the appended bibliography.

#The predatory cone snails (Conus) have developed a unique biological strategy. Their venom contains relatively small peptides that are targeted to various neuromuscular receptors and may be equivalent in their pharmacological diversity to the alkaloids of plants or secondary metabolites of microorganisms. Many of these peptides are among the smallest nucleic acid-encoded translation products having defined conformations, and as such, they are somewhat unusual. Peptides in this size range normally equilibrate among many conformations. Proteins having a fixed conformation are generally much larger.

#FIG. 1 shows the time-dependent inhibition of audiogenic seizures by Con R following intracerebroventricular (i.c.v.) administration to Frings audiogenic mice.

#FIG. 2 shows the ability of conantokins (Con R (♦), Con T (▪) Con G (◯)) to block audiogenic seizures in a dose-dependent manner following i.c.v. administration to Frings audiogenic mice.

#FIG. 3 shows the dose-dependent reduction in seizure severity following i.c.v. administration to Frings audiogenic mice for conantokins (Con R (♦), Con T (▪) Con G (◯)).

#The present invention is directed to conantokin peptides, conantokin peptide derivatives and conantokin peptide chimeras, referred to collectively as conantokins (unless the context dictates otherwise), having 10-30 amino acids, including preferably one to two or more γ-carboxyglutamic acid residues. The conantokins are useful for the treatment of neurologic and psychiatric disorders, such as anticonvulsant agents, as neuroprotective agents or for the management of pain, e.g. as analgesic agents. Neurologic disorders and psychiatric disorders as used herein are intended to include such disorders as grouped together in The Merck Manual of Diagnosis and Therapy, inclusive of the disorders discussed herein.

#More specifically, the present invention is directed to conantokins which are useful for the treatment and alleviation of epilepsy and as a general anticonvulsant agent. The present invention is also directed to conantokins which are useful for reducing neurotoxic injury associated with conditions of hypoxia, anoxia or ischemia which typically follows stroke, cerebrovascular accident, brain or spinal cord trauma, myocardial infarct, physical trauma, drowning, suffocation, perinatal asphyxia, or hypoglycemic events. The present invention is further directed to conantokins useful for treating neurodegeneration associated with Alzheimer's disease, senile dementia, Amyotrophic Lateral Sclerosis, Multiple Sclerosis, Parkinson's disease, Huntington's disease, Down's Syndrome, Korsakoff's disease, schizophrenia, AIDS dementia, multi-infarct dementia, Binswanger dementia and neuronal damage associated with uncontrolled seizures. The present invention is also directed to conantokins which are useful for treating chemical toxicity, such as addiction, drug craving, alcohol abuse, morphine tolerance, opioid tolerance and barbiturate tolerance. The present invention is further directed to conantokins useful for treating psychiatric disorders, such as anxiety, major depression, manic-depressive illness, obsessive-compulsive disorder, schizophrenia and mood disorders (such as bipolar disorder, unipolar depression, dysthymia and seasonal effective disorder). The conantokins are also useful for treating ophthalmic disorders. The present invention is also directed to conantokins useful for treating additional neurological disorders, such as dystonia (movement disorder), sleep disorder, muscle relaxation and urinary incontinence. In addition, the conantokins are useful for memory/cognition enhancement, i.e., treating memory, learning or cognitive deficits. The present invention is also useful in the treatment of HIV infection. Finally, the present invention is directed to conantokins useful for controlling pain, e.g. as analgesic agents, and the treatment of migraine, acute pain or persistent pain. They can be used prophylactically and also to relieve the symptoms associated with a migraine episode.

#The present invention is directed to conantokin peptides, which include but are not limited to G, T, L, R, S1, Oc, Gm, Ca2, Cal and Qu. Conantokin G (Con G) has the formula Gly-Glu-Xaa1-Xaa1-Leu-Gln-Xaa2-Asn-Gln-Xaa2-Leu-Ile-Arg-Xaa2-Lys-Ser-Asn (SEQ ID NO:1), wherein Xaa1 and Xaa2 are preferably γ-carboxyglutamic acid (Gla). The C-terminus contains a carboxyl or an amide, preferably an amide group. Conantokin T (Con T) has the formula Gly-Glu-Xaa1-Xaa1-Tyr-Gln-Lys-Met-Leu-Xaa2-Asn-Leu-Arg-Xaa2-Ala-Glu-Val-Lys-Lys-Asn-Ala (SEQ ID NO:2), wherein Xaa1 and Xaa2 are preferably γ-carboxyglutamic acid. The C-terminus contains a carboxyl or an amide, preferably an amide group. Conatokin L (Con L), has the formula Gly-Glu-Xaa1-Xaa1-Val-Ala-Lys-Met-Ala-Ala-Xaa2-Leu-Ala-Arg-Xaa2-Asp-Ala-Val-Asn (SEQ ID NO:3), wherein Xaa1 and Xaa2 are preferably γ-carboxyglutamic acid. The C-terminus contains a carboxyl or an amide, preferably an amide group. Conantokin R (Con R) has the formula: Gly-Glu-Xaa1-Xaa1-Val-Ala-Lys-Met-Ala-Ala-Xaa2-Leu-Ala-Arg-Xaa2-Asn-Ile-Ala-Lys-Gly-Cys-Lys-Val-Asn-Cys-Tyr-Pro (SEQ ID NO:4), wherein Xaa1 and Xaa2 are preferably γ-carboxyglutamic acid. The C-terminus contains a carboxyl or an amide, preferably a carboxyl group. The cysteine residues form a disulfide bridge. Conantokin S1 (Con S1) has the formula: Gly-Asp-Xaa1-Xaa1-Tyr-Ser-Lys-Phe-Ile-Xaa2-Arg-Glu-Arg-Xaa2-Ala-Gly-Arg-Leu-Asp-Leu-Ser-Lys-Phe-Pro (SEQ ID NO:5), wherein Xaa1 and Xaa2 are preferably γ-carboxyglutamic acid. The C-terminus contains a carboxyl or amide, preferably a carboxyl group. Conantokin Oc (Con Oc) has the formula: Gly-Glu-Xaa1-Xaa1-Tyr-Arg-Lys-Ala-Met-Ala-Xaa2-Leu-Glu-Ala-Lys-Lys-Ala-Gln-Xaa2-Ala-Leu-Lys-Ala (SEQ ID NO:6), wherein Xaa1 and Xaa2 are preferably γ-carboxyglutamic acid. The C-terminus contains a carboxyl or amide, preferably an amide group. Conantokin Gm (Con Gm) has the formula: Gly-Ala-Lys-Xaa1-Asp-Arg-Asn-Asn-Ala-Xaa2-Ala-Val-Arg-Xaa2—Arg-Leu-Glu-Glu-Ile (SEQ ID NO:7), wherein Xaa1 and Xaa2 are preferably γ-carboxyglutamic acid. The C-terminus contains a carboxyl or amide, preferably an amide group. Conantokin Ca2 (Con Ca2) has the formula: Gly-Tyr-Xaa1-Xaa1-Asp-Arg-Xaa2-Ile-Ala-Xaa2-Thr-Val-Arg-Xaa2-Leu-Glu-Glu-Ala (SEQ ID NO:8), wherein Xaa1 and Xaa2 are preferably γ-carboxyglutamic acid. The C-terminus contains a carboxyl or amide, preferably an amide group. Conantokin Qu (Con Qu) has the formula: Gly-Tyr-Xaa1-Xaa1-Asp-Arg-Xaa2-Val-Ala-Xaa2-Thr-Val-Arg-Xaa2-Leu-Asp-Ala-Ala (SEQ ID NO:9), wherein Xaa1 and Xaa2 are preferably γ-carboxyglutamic acid. The C-terminus contains a carboxyl or amide, preferably an amide group. Conantokin Ca1 (Con Ca1) has the formula: Gly-Asn-Asp-Val-Asp-Arg-Lys-Leu-Ala-Xaa2-Leu-Xaa2-Xaa2-Leu-Tyr-Xaa2-Ile (SEQ ID NO:68), wherein Xaa2 is preferably γ-carboxyglutamic acid. The C-terminus contains a carboxyl or amide, preferably an amide group.