JPH10330399A - Neutral transmission polypeptide - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject new compound useful as an analgesic, a preventive and a therapeutic agent for various nervous diseases, etc., comprising a neutral transmission polypeptide having a specific amino acid sequence, having ligand actions of opioid-like receptor, hardly being subjected to enzymolysis. SOLUTION: This new neutral transmission polypeptide is shown by the formula [R<1> is H, a monofunctional amino acid residue, a monofunctional peptide residue, a halogen, a lower alkyl or an acyl; R<2> is H, OH, a lower alkoxy; X<1> , X<2> , Y<1> , Y<2> , Z<1> and Z<2> are each an amino acid residue (with the proviso that a case in which simultaneously R<1> is H and R<2> is OH, X<1> and X<2> are each an alanine residue, Y<1> and Y<2> are each an arginine residue and Z<1> and Z<2> are each a lysine residue)] and is useful as a therapeutic agent and a preventive for various nervous diseases or an analgesic, etc. The peptide is obtained by successively condensing amino acids from peptide carboxyl ends by a solid- phase synthesis method or a liquid-phase synthetic method which is an ordinary peptide synthesis method.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a novel neurotransmitter polypeptide having excellent pharmacological action and a salt thereof.

[0002]

BACKGROUND OF THE INVENTION Nociceptin (or also known as orphanin FQ) has recently been discovered as a ligand for opioid-like receptors (Neur).
oscience Letter, 223 (1997) 113-116). Nociceptin is a polypeptide consisting of 17 amino acid residues and is considered to be involved in pain transmission, and its action is considered to have an analgesic action different from that of morphine.

[0003] However, nociceptin undergoes enzymatic degradation in vivo, and the degradation product stimulates nerve cells to release substance P, which is a pain transmitter, and exhibits a pain action. In particular, at a low concentration of nociceptin, the effect of enzymatic degradation is remarkably exhibited, and a pain effect is exhibited. Therefore, when attention is paid to the analgesic effect, a compound which is hardly susceptible to enzymatic degradation in a living body and exhibits an analgesic activity even at a low concentration is desired.

[0004]

DISCLOSURE OF THE INVENTION The present invention reduces the nociceptive effect of nociceptin by reducing the nociceptive effect of nociceptin, as it is less susceptible to enzymatic degradation in vivo and less likely to produce degradation products. The present invention provides a polypeptide represented by the following general formula (1) and a salt thereof, which have an analgesic effect. This compound of the present invention is considered to be an analgesic or a preventive or therapeutic agent for various neurological diseases.

[0005]

Embedded image R ¹ -Phe-Gly-Gly-Phe-Thr-Gly-X ¹ -Y ¹ -Z ¹ -Ser-X ² -Y ² -Z ² -Leu-Ala-Asn-Gln-R ²・・ ・ (1)

[However, in the general formula (1), R ¹ , R ² ,
X ¹ , X ² , Y ¹ , Y ² , Z ¹ and Z ² are as follows. R ¹ : hydrogen atom, monovalent amino acid residue, monovalent peptide residue, halogen atom, lower alkyl group, acyl group. R ² : a hydrogen atom, a hydroxyl group, or a lower alkoxy group. ^{X 1, X 2, Y 1} , Y 2, Z 1, Z 2: independently amino acid residues. (However, at the same time, R ¹ is a hydrogen atom, R ² is a hydroxyl group, X
¹ and X ² are both alanine residues, Y ¹ and Y ²
Is an arginine residue, and Z ¹ and Z ² are all lysine residues. )]

[0007]

BEST MODE FOR CARRYING OUT THE INVENTION In the above description and the following description of the present invention, "amino acid" means both a naturally occurring amino acid and a synthetic amino acid which does not naturally occur. In addition to α-amino acids, β-amino acids and other amino acids are also meant. In the case of α-amino acid, it means not only L-amino acid but also D-amino acid.
The amino acid residues constituting the polypeptide of the present invention refer to residues of L-type α-amino acids unless otherwise specified. Some amino acid residues may be preferably D-form α-amino acids, as noted. However, the amino acids (residues) in the present invention are not limited to these preferred amino acids (residues).

[0008] The term "halogen atom" means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom. When the organic group is “lower”, it means that the number of carbon atoms is 1 to 6.
The “lower alkyl group” may be linear or branched, and suitable examples thereof include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group,
Examples include a t-butyl group, a pentyl group, and a hexyl group. The "lower alkoxy group" may be linear or branched, and suitable examples thereof include a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, an isobutoxy group and a t-butoxy group. Is raised. The “acyl group” may be linear or branched, and suitable examples thereof include a formyl group,
Examples include an acetyl group, a propionyl group, a butyryl group, and an isobutyryl group. Preferred acyl groups are those that are useful in protecting groups.

The salt of the polypeptide represented by the general formula (1) includes an acid addition salt derived from the polypeptide and an inorganic acid or an organic acid. Such salts include, for example, hydrochloride, hydrobromide, sulfate, phosphate, methanesulfonate, p-toluenesulfonate, oxalate, tartrate, citrate, maleic acid Salts, fumarate, succinate, lactate, glutarate, acetate, trifluoroate, various amino acid salts and the like.

The salts of the polypeptide represented by the general formula (1) include salts formed from the polypeptide and a base. Such salts include, for example, salts formed from alkali metals (eg, sodium, potassium), alkaline earth metals (eg, calcium, magnesium), ammonium and substituted ammonium (eg, dimethylammonium, triethylammonium) and the like. There is.

In the polypeptide of the present invention, R ¹ is a hydrogen atom, a monovalent amino acid residue, a monovalent peptide residue,
And acyl groups are preferred. As the monovalent peptide residue, a monovalent peptide residue having 2 to 8, preferably 2 to 4 amino acid residues is preferable. As the acyl group, an acyl group useful as a protecting group such as a t-butyloxycarbonyl group and a 9-fluorenyloxycarbonyl group is preferable.
Particularly preferred R ¹ is a hydrogen atom. As R ² , a hydroxyl group is particularly preferred.

It is preferable that at least one of X ¹ and X ² is an alanine residue, and it is particularly preferable that both are an alanine residue. It is preferable that at least one of Y ¹ and Y ² is a D-arginine residue or a leucine residue. Furthermore, when one is a D-arginine residue, the other is any of a D-arginine residue, an arginine residue and a leucine residue, and when one is a leucine residue, the other is an arginine residue. And leucine residues. Particularly preferably, all are D-arginine residues or both are leucine residues. Z ¹ , Z ²
It is preferable that at least one is a leucine residue or a lysine residue, and it is particularly preferable that all are leucine residues, all are lysine residues, and one is a leucine residue and the other is a lysine residue.

Particularly preferred polypeptides are all R
¹ is a hydrogen atom and R ² is a hydroxyl group, and -X ¹ -Y ¹
A polypeptide in which the combination of -Z ¹ -and -X ² -Y ² -Z ² -is a combination shown in Table 1 below (hereinafter, P-
1 to P-7). For example, the above P-1 to P
The following shows the entire sequence of -3.

[0014]

[Table 1]

[0015]

Embedded image P-1: Phe-Gly-Gly-Phe-Thr-Gly-Ala-D-Arg-
Leu-Ser-Ala-D-Arg-Leu-Leu-Ala-Asn-Gln. P-2: Phe-Gly-Gly-Phe-Thr-Gly-Ala-Leu-Leu-Ser-Al
a-Leu-Leu-Leu-Ala-Asn-Gln. P-3: Phe-Gly-Gly-Phe-Thr-Gly-Ala-D-Arg-Lys-Ser-
Ala-D-Arg-Lys-Leu-Ala-Asn-Gln.

The polypeptide represented by the general formula (1) is
For example, it can be produced by a general peptide synthesis method as described in “Basic and Experimental Peptide Synthesis” (Maruzen Co., Ltd.). That is, the polypeptide represented by the general formula (1) can be produced by sequentially condensing amino acids from the peptide carboxyl terminus by the peptide liquid phase synthesis method or the peptide solid phase synthesis method. Alternatively, after producing a fragment of the desired polypeptide by peptide liquid phase synthesis or peptide solid phase synthesis,
The polypeptide represented by the general formula (1) can be produced by joining these by a peptide liquid phase synthesis method or a peptide solid phase synthesis method. As the amino acid raw material to be used, the amino group of the amino acid is, for example, t-
Those protected with a protecting group such as a butyloxycarbonyl group (Boc) and a 9-fluorenylmethyloxycarbonyl group (Fmoc) are preferred. Further, it is preferable that the side chain functional groups of the amino acid raw materials used are each protected with a preferable protecting group.

The amino acid side chain protecting group includes, for example, t
-Butyloxycarbonyl group (Boc), t-butyl group (tBu), trityl group (Trt), benzyl group (Bz
1) 2,2,5,7,8-pentamethylchromansulfonyl group (Pmc) and the like. Examples of the condensing agent for forming a peptide bond include N, N-dicyclohexylcarbodiimide (DCC), 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide (WSC), and benzotriazol-1-yl- Oxy-tris- (dimethylamino) -phosphonium hexafluorophosphate (BOP), benzotriazol-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate (pyBOP), 2-
(1H-benzotriazol-1-yl) -1,1,1
Examples thereof include 3,3-tetramethyluronium hexafluorophosphate (HBTU) and 2- (1H-benzotriazol-1-yl) -1,1,3,3-tetramethyluronium tetrafluoroborate.

Further, N-hydroxybenzotriazole (HOBt) and the above-mentioned condensing agent can be mixed and used in a preferable ratio. Examples of a base used for forming a peptide bond include triethylamine, diisopropylethylamine (DIEA) and the like. Boc and Fmoc, protecting groups for the amino terminal amino group of a peptide or amino acid, can be removed with trifluoroacetic acid (TFA) or piperidine, respectively. The protecting group for the side chain functional group of the amino acid residue of the peptide is
For example, it can be removed by TFA, hydrogen fluoride (HF), trifluoromethanesulfonic acid, or the like.

In the peptide solid phase synthesis method, as a method for releasing a peptide or a peptide having a protective group on a side chain functional group of an amino acid residue from a peptide solid phase synthesis resin, for example, TFA is used. Can be used. The elimination of the peptide from the peptide solid phase resin and the elimination of the protecting group of the side chain functional group of the amino acid residue can be performed simultaneously in the same reaction system. Alternatively, they can be performed independently. Examples of the peptide solid phase synthesis resin for peptide solid phase synthesis include, for example, those obtained by crosslinking chloromethylpolystyrene-divinylbenzene with polystyrene,
A commercially available product such as a product obtained by crosslinking p-benzyloxybenzyl alcohol (hereinafter referred to as p-benzyloxybenzyl alcohol polystyrene) can be used.

The polypeptide of interest or its intermediate is
For example, isolation and purification can be performed by various methods such as ion chromatography, gel filtration chromatography, reverse phase chromatography, normal phase chromatography, recrystallization, extraction, and fractional crystallization. Further, the thus-obtained polypeptide, which is represented by the general formula (1), can be converted into each salt by a conventional method.

The compounds (polypeptides and salts thereof) of the present invention have the same physiological action on nerves as nociceptin. Therefore, the compound of the present invention is useful as an active ingredient of a medicament, particularly useful as an agent for preventing or treating a neurological disease and as an analgesic.

When the compound of the present invention is used as a pharmaceutical, the compound of the present invention is used as an active ingredient, and a pharmaceutically acceptable carrier such as an organic or inorganic solid or liquid excipient suitable for oral administration, parenteral administration or external use. As a mixture with conventional pharmaceutical preparations containing the compound.
The pharmaceutical preparation may be in the form of solid such as tablets, granules, powders, capsules and the like, or may be in the form of liquids, suspensions, syrups, emulsions and liquids of lemonade. If necessary, auxiliaries, stabilizers, wetting agents and other conventional additives may be added to the above-mentioned preparations, for example, lactose, citric acid, tartaric acid, stearic acid, magnesium stearate, clay, sucrose, corn starch, talc, gelatin, Agar, pectin, peanut oil, olive oil, cocoa oil, ethylene glycol and the like may be blended.

The dose of the compound of the present invention varies depending on the age of the patient, the type of the disease or condition, the compound of the present invention to be applied, and the like, but is generally 0.01 mg to 500 mg per day. A dose in the range or even higher may be administered to the patient. In treating various diseases, the average dose of the compound of interest of the present invention was 0.05 mg,
0.1 mg, 0.25 mg, 0.5 mg, 1 mg, 20
mg, 50 mg, 100 mg, etc.

[0024]

EXAMPLES Hereinafter, the present invention will be described specifically with reference to Examples, but the present invention is not limited to these Examples.

Example 1 Synthesis of Polypeptide P-1 Acetate (Synthesis 1) Synthesis of Fmoc-glutamine (Trt) -p-benzyloxybenzyl alcohol polystyrene 2.7 g of Fmoc-glutamine (Trt) (4.4 mm)
ol) and 454 mg (0.67 mmol) of DCC were reacted in 30 ml of dichloromethane at an ice temperature for 15 minutes. After completion of the reaction, dichloromethane was distilled off under reduced pressure, and the residue was dissolved in N, N-dimethylformamide (DMF). 82 mg of this solution and 4-dimethylaminopyridine
(0.67 mmol) was added to 1 g of p-benzyloxybenzyl alcohol polystyrene (crosslinking ratio 0.67 mmol /
g) and mixed for one day to remove DMF, to obtain the desired Fmoc-glutamine (Trt) -p-benzyloxybenzyl alcohol polystyrene.

(Synthesis 2) Phenylalanyl-glycyl-glycyl-phenylalanyl-threonyl (tBu) -glycyl-alanyl-D
-Arginyl (Pmc) -leucyl-serinyl (tB
u) -Alanyl-D-arginyl (Pmc) -leucyl-leucyl-alanyl-asparazinyl (Trt) -glutaminyl (Trt) -p-benzyloxybenzyl alcohol Synthesis of polystyrene

Approximately 250 mg of Fmoc-glutamine (Trt) -p-benzyloxybenzyl alcohol polystyrene obtained in Synthesis 1 was used, and amino acids were sequentially condensed. A 20% piperidine / DMF solution was used to remove Fmoc, and 133 mg (0.25 mmol) of PyBOP and H
OBt 15.3 mg (0.1 mmol), DIEA
86 μl (0.5 mmol) was used. Table 2 shows the order in which the Fmoc-amino acids used in each case are used for condensation.

Finally, the amino-terminal Fmoc was reduced to 20%.
After removal with piperidine / DMF, the solvent is removed and the target compound, phenylalanyl-glycyl-glycyl-phenylalanyl-threonyl (tBu) -glycyl-alanyl-D-arginyl (Pmc) -leucyl-serinyl ( tBu) -alanyl-D-arginyl (Pm
c) -Leucyl-leucyl-alanyl-asparazinyl (Trt) -glutaminyl (Trt) -p-benzyloxybenzyl alcohol Polystyrene was obtained.

[0029]

[Table 2]

(Synthesis 3) Synthesis of TFA salt of P-1 After sufficiently drying the product obtained in Synthesis 2, TFA:
Mixed solution 3 of triisopropylsilane: water = 94: 2: 4
0 ml was added, and the mixture was reacted at room temperature for about 2 hours. After removing the solid, the liquid was distilled off from the remaining liquid under reduced pressure, and diethyl ether was added to the residue. The resulting white precipitate is filtered off,
This was dissolved in an acetic acid / water mixed solvent. This is freeze-dried to obtain the target polypeptide P-1 (phenylalanyl-glycyl-glycyl-phenylalanyl-).
About 200 mg of a crude product (threonyl-glycyl-alanyl-D-arginyl-leucyl-serinyl-alanyl-D-arginyl-leucyl-leucyl-alanyl-asparadinyl-glutamine) was obtained. This crude product was purified by C18 reverse phase column chromatography using a mixed solvent of 0.1% TFA / water and 0.1% TFA / acetonitrile to obtain 70 mg of P-1 TFA salt.

(Synthesis 4) Synthesis of P-1 acetate 70 mg of P-1 TFA salt obtained in Synthesis 3 was 5 wt%.
It was dissolved in an aqueous acetic acid solution and replaced with an acetate type by a strong base exchange resin column previously treated with a 20 wt% aqueous acetic acid solution. The obtained acetic acid solution is freeze-dried to obtain P-1.
60 mg of acetate were obtained.

[Example 2] Identification of P-1 acetate by amino acid analysis A part of the P-1 acetate obtained in Example 1 was treated with 6N HCl for 1 hour.
After hydrolysis at 40 ° C. for 4 hours, the amino acid composition was analyzed. Table 3 shows the results.

[0033]

[Table 3]

Example 3 Synthesis of Polypeptide P-3 Acetate (Synthesis 5) Phenylalanyl-glycyl-glycyl-phenylalanyl-threonyl (tBu) -glycyl-alanyl-D
-Arginyl (Pmc) -lysinyl (Boc) -serinyl (tBu) -alanyl-D-arginyl (Pmc)-
Synthesis of lysinyl (Boc) -leucyl-alanyl-asparazinyl (Trt) -glutaminyl (Trt) -p-benzyloxybenzyl alcohol polystyrene

Fmoc-glutamine (Trt) -p-benzyloxybenzyl alcohol obtained in Synthesis 1
About 250 mg of polystyrene was used, and amino acids were sequentially condensed from this. A 20% piperidine / DMF solution was used to remove Fmoc, and 133 mg (0.25 mmol) of PyBOP and H
OBt 15.3 mg (0.1 mmol), DIEA
86 μl (0.5 mmol) was used. Table 4 shows the order in which the Fmoc-amino acids used in each case are used for the condensation.

Finally, the amino-terminal Fmoc is reduced to 20%
After removal with piperidine / DMF, the solvent was removed to remove the target compound, phenylalanyl-glycyl-glycyl-phenylalanyl-threonyl (tBu) -glycyl-alanyl-D-arginyl (Pmc) -lysinyl (Bmc).
oc) -serinyl (tBu) -alanyl-D-arginyl (Pmc) -lysinyl (Boc) -leucyl-alanyl-asparazinyl (Trt) -glutaminyl (Tr
t) -p-Benzyloxybenzyl alcohol polystyrene was obtained.

[0037]

[Table 4]

(Synthesis 6) Synthesis of TFA salt of P-3 After sufficiently drying the product obtained in Synthesis 5, TFA:
Mixed solution 3 of triisopropylsilane: water = 94: 2: 4
0 ml was added, and the mixture was reacted at room temperature for about 2 hours. After removing the solid, the liquid was distilled off from the remaining liquid under reduced pressure, and diethyl ether was added to the residue. The resulting white precipitate is filtered off,
This was dissolved in an acetic acid / water mixed solvent. This is freeze-dried to give the desired polypeptide, P-3 (phenylalanyl-glycyl-glycyl-phenylalanyl-threonyl-glycyl-alanyl-D-arginyl-lidinyl-serinyl-alanyl-D-arginyl-lidinyl). -Leucyl-alanyl-asparadinyl-glutamine). This crude product was purified by C18 reverse phase column chromatography using a mixed solvent of 0.1% TFA / water and 0.1% TFA / acetonitrile to obtain 95 mg of P-3 TFA salt.

(Synthesis 7) Synthesis of P-3 acetate salt 95 mg of P-3 TFA salt obtained in Synthesis 6 was dissolved in a 5% acetic acid aqueous solution, and a strong base exchange resin column previously treated with a 20% acetic acid aqueous solution was used. Was replaced with the acetate type. The desired P-3 was obtained by freeze-drying the obtained acetic acid solution.
85 mg of acetate were obtained.

[Example 4] Identification of P-3 acetate by amino acid analysis A part of the P-3 acetate obtained in Example 3 was treated with 6N HCl for 1 hour.
After hydrolysis at 40 ° C. for 4 hours, the amino acid composition was analyzed. Table 5 shows the results.

[0041]

[Table 5]

Example 5 Synthesis of Polypeptide P-2 Acetate (Synthesis 8) Phenylalanyl-glycyl-glycyl-phenylalanyl-threonyl (tBu) -glycyl-alanyl-leucyl-leucyl-serinyl (tBu)- Alanyl-D
Synthesis of -leucyl-leucyl-leucyl-alanyl-asparazinyl (Trt) -glutaminyl (Trt) -p-benzyloxybenzyl alcohol polystyrene

Fmoc-glutamine (Trt) -p-benzyloxybenzyl alcohol obtained in Synthesis 1
About 250 mg of polystyrene was used, and amino acids were sequentially condensed from this. A 20% piperidine / DMF solution was used to remove Fmoc, and 133 mg (0.25 mmol) of PyBOP and H
OBt 15.3 mg (0.1 mmol), DIEA
86 μl (0.5 mmol) was used. Table 6 shows the order in which the Fmoc-amino acids used in each case are used for the condensation.

Finally, the amino-terminal Fmoc was reduced to 20%
After removal with piperidine / DMF, the solvent is removed and the desired phenylalanyl-glycyl-glycyl-phenylalanyl-glycyl-threonyl (tBu) is removed.
-Glycyl-alanyl-leucyl-leucyl-serinyl (tBu) -alanyl-leucyl-leucyl-leucyl-alanyl-asparadinyl (Trt) -glutaminyl (Trt) -p-benzyloxybenzyl alcohol
Polystyrene was obtained.

[0045]

[Table 6]

(Synthesis 9) Synthesis of TFA salt of P-2 After sufficiently drying the product obtained in Synthesis 8, TFA:
Mixed solution 3 of triisopropylsilane: water = 94: 2: 4
0 ml was added, and the mixture was reacted at room temperature for about 2 hours. After removing the solid, the liquid was distilled off from the remaining liquid under reduced pressure, and diethyl ether was added to the residue. The resulting white precipitate is filtered off,
This was dissolved in an acetic acid / water mixed solvent. This is freeze-dried to give the desired polypeptide P-2 (phenylalanyl-glycyl-glycyl-phenylalanyl-).
About 130 mg of a crude product (threonyl-glycyl-alanyl-leucyl-leucyl-serinyl-alanyl-leucyl-leucyl-leucyl-alanyl-asparadinyl-glutamine) was obtained. This crude product is treated with 0.1% TFA /
Purification was performed by C18 reverse phase column chromatography using water and a mixed solvent of 0.1% TFA / acetonitrile to obtain 26 mg of the desired TFA salt of P-2.

Example 6 Identification of TFA Salt of P-2 by Amino Acid Analysis A part of the TFA salt of P-2 obtained in Example 5 was converted to 6N HCl.
After hydrolysis at 140 ° C. for 4 hours, the amino acid composition was analyzed. Table 7 shows the results.

[0048]

[Table 7]

[0049]

Industrial Applicability A novel polypeptide useful as a therapeutic or preventive agent for various neurological diseases or as an analgesic has been synthesized.

[0050]

[Sequence list] SEQ ID NO: 1 Sequence length: 17 Sequence type: Amino acid Topology: Linear Sequence type: Peptide Sequence features Characteristic symbol: unusual amino acid Location: 8 and 12 Other information: Arg = D-Arg Sequence: Phe Gly Gly Phe Thr Gly Ala Arg Leu Ser Ala Arg Leu Leu Ala Asn 5 10 15 Gln

SEQ ID NO: 2 Sequence length: 17 Sequence type: Amino acid Topology: Linear Sequence type: Peptide Sequence: Phe Gly Gly Phe Thr Gly Ala Leu Leu Ser Ala Leu Leu Leu Ala Asn 5 10 15 Gln

SEQ ID NO: 3 Sequence length: 17 Sequence type: amino acid Topology: linear Sequence type: peptide Sequence characteristics Characteristic symbol: unusual amino acid Location: 8 and 12 Other information: Arg = D-Arg sequence: Phe Gly Gly Phe Thr Gly Ala Arg Lys Ser Ala Arg Lys Leu Ala Asn 5 10 15 Gln

Claims (7)

[Claims] 1. A polypeptide represented by the general formula (1) or a salt thereof. Embedded image R ¹ -Phe-Gly-Gly-Phe-Thr-Gly-X ¹ -Y ¹ -Z ¹ -Ser-X ² -Y ² -Z ² -Leu-Ala-Asn-Gln-R ²・・ ・ (1) [However, in the general formula (1), R ¹ , R ² , X ¹ , X ² ,
Y ¹ , Y ² , Z ¹ and Z ² are as follows. R ¹ : hydrogen atom, monovalent amino acid residue, monovalent peptide residue, halogen atom, lower alkyl group, acyl group. R ² : a hydrogen atom, a hydroxyl group, or a lower alkoxy group. ^{X 1, X 2, Y 1} , Y 2, Z 1, Z 2: independently amino acid residues. (However, at the same time, R ¹ is a hydrogen atom, R ² is a hydroxyl group, X
¹ and X ² are both alanine residues, Y ¹ and Y ²
Is an arginine residue, and Z ¹ and Z ² are all lysine residues. )] 2. The polypeptide according to claim 1, wherein at least one of X ¹ and X ² is an alanine residue, or a salt thereof. 3. The method according to claim 1, wherein at least one of Y ¹ and Y ² is a D-argin residue or a leucine residue.
Or a salt thereof. 4. The polypeptide according to claim 1, 2 or 3, wherein at least one of Z ¹ and Z ² is a leucine residue or a lysine residue, or a salt thereof. 5. A pharmaceutical comprising the polypeptide of claim 1, 2, 3 or 4 or a salt thereof as an active ingredient. 6. A preventive or therapeutic agent for a neurological disease comprising the polypeptide of claim 1, 2, 3 or 4 or a salt thereof as an active ingredient. 7. An analgesic comprising the polypeptide according to claim 1, 2, 3 or 4 or a salt thereof as an active ingredient.