Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
1996-07-05
2004-03-30
Kemmerer, Elizabeth (Department: 1647)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C514S018700, C530S300000, C530S323000, C530S345000, C435S007100
Reexamination Certificate
active
06713443
ABSTRACT:
The subject of the present invention is compounds having the property of modifying serotoninergic transmission as well as the diagnostic and therapeutic applications of these compounds.
The cerebral serotoninergic system is a cerebral and peripheral neurotransmission system which uses serotonin or 5-hydroxytryptamine (5-HT) which was discovered during the course of 1949/50.
At the central level, this system is special in that it is extremely centralized (all the cellular bodies are located in the posterior region of the brain, the raphe) and where it projects into practically all the regions of the brain. It is characterized by an extremely high level of varicosity (or equivalent of neuronal ends) along the axons; this arrangement multiplies its points of interaction with the other cerebral neuronal systems. Furthermore, a very large part of this varicosity does not exhibit any synaptic profile, that is to say that the 5-HT released by these “ends” will diffuse and reach the targets (receptors) located at a certain distance; this mechanism requires the use of special receptors having a high affinity for the amine. This structural arrangement is quite favourable for a function of controlling the entire neuronal cells of the brain, and consequently for an essential role in maintaining the homeostasis of the central nervous system.
To exert this control, the 5-HT system uses a large variety of specific receptors. Several families are indeed involved some of which are well characterized (5-HT
1
, 5-HT
2
, 5-HT
3
, 5-HT
4
) and others identified more recently are still not well known (5-HT
5
, 5-HT
6
, 5-HT
7
). Some of them are represented by numerous subtypes; such is the case in particular for the 5-HT
1
−
family, characterized by a nanomolar affinity of 5-HT for these sites, and which comprises the subtypes 5-HT
1A,B,D,E,F
.
The 5-HT
1B
and 5-HT
1D
type receptors are located on the serotoninergic and non-serotoninergic ends where they modulate the release of the neurotransmitter contained in these ends, in particular they can regulate the release of 5-HT itself (autoreceptors) and play, in this case, a decisive role in the activity of the serotoninergic neurotransmission.
From a fundamental point of view, the serotoninergic system is involved in numerous physiological functions and in numerous pathologies, and especially in depressive syndrome.
Depression is a psychiatric disorder which is still poorly known in spite of numerous studies which have been devoted to it. However, it is now quite clear that most, if not all, depressions involve the serotoninergic system and, especially, it is generally accepted that there is a relationship between a serotoninergic deficiency and suicide.
In addition, antidepressant drugs interact, for a large number of them, with the serotoninergic system and the most recent, which are the most effective and which possess the least undesirable effects, are most often of the “serotoninergic” type. These substances all result, by various mechanisms, in facilitating serotoninergic transmission (inhibitors of monoamine oxidases, inhibitors of recapture, 5-HT
1A
agonists). However, on the one hand, their efficacy is limited and, on the other hand, they still possess, for many of them, substantial side effects, and finally, their delayed action is substantial (>2 weeks).
Recent results in the literature and from the inventors indicate that the 5-HT
1B/1D
receptors might play a major role in the depressive syndrome and in the mechanism of action of antidepressants. It has indeed been shown that they not only modulate the liberation of acetylcholine, but they also modulate that of 5-HT itself and thereby effectively regulate the serotoninergic transmission of which the importance in the depressive syndrome is known. Furthermore, they are the target of antidepressants which interact probably in a noncompetitive manner; in other words, the antidepressants are thought to recognize a separate site of the 5-HT
1B/1D
receptors, but closely interactive with the latter.
The work of the inventors has allowed the identification of a cerebral endogenous compound which recognizes a receptor site capable of interacting with the functioning of certain 5-HT receptors, in particular the 5-HT
1B/1D
receptors which modulate the release of 5-HT itself.
The cerebral endogenous compound identified is a tetrapeptide of sequence:
Leu-Ser-Ala-Leu (sequence LSAL SEQ ID NO:4).
The inventors also tested the activity of peptides comprising part of the LSAL sequence or the modified LSAL sequence and showed that these compounds still had a good activity on the 5-HT
1B/1D
receptors. In general, a modification (for example an acetylation) of the NH
2
-terminal end leads to a compound having a lower ligand activity on the 5-HT receptor, whereas modifications of the COOH end make it possible to obtain a peptide which still has a substantial activity.
For example, the addition of the sequence Gly-Gly-Gly-Tyr to the COOH end of the LSAL sequence makes it possible to obtain a compound still having a substantial activity. However, the addition of the same sequence, but whose Tyr residue is iodinated, leads to a compound no longer having a ligand activity for the 5-HT receptor, probably because of the steric hindrance due to the large size of the iodine atoms which prevent the binding of the peptide thus modified to its receptor.
The subject of the invention is thus a compound of peptide sequence
X Leu Y
in which X represents H (SEQ ID NO:1) or Ala (SEQ ID NO:2) or Leu-Ser-Ala (SEQ ID NO:3), Y represents OR, or a peptide sequence having from 1 to 10 amino acids, whose carboxy-terminal end is amidated by an NH
2
group or esterified by a substituted or unsubstituted hydroxycarbyloxy residue, with the proviso that X and Y do not simultaneously represent H and OH, respectively as well as the corresponding compounds in which the peptide bonding group —CO—NH— is replaced by a bonding group resistant to the enzymatic degradation of proteases, or in which the peptide backbone comprises one or more intercalated groups making the peptide bond resistant to enzymatic degradation.
Thus, the peptide bonding group (—CO—NH—) is advantageously replaced by a bonding group —CO—NR′—, —CR
1
R
2
—CR
3
R
4
—, —CO—CR
1
R
2
—, R
1
, R
2
, R
3
and R
4
, which are identical or different, representing H or a C
1
-C
6
alkyl group, especially a methyl group, and R′ representing a C
1
-C
6
alkyl group.
Among the groups which can be intercalated into the peptide backbone, the following groups may be mentioned —CR
1
R
2
—, —NR
1
— and —O—, R
1
and R
2
being defined as above.
Hydroxycarbyloxy residue is understood to mean especially an alkyloxy, alkenyloxy or alkynyloxy group, with a linear or branched chain, having from 1 to 10 carbon atoms, unsubstituted or substituted by one or more groups selected from OH, NH
2
, NO
2
, Cl, Br, F, CF
3
for example the group OCH
3
, OC
2
H
5
, OCHOH—CH
3
, OCHOH—CH
2
OH, OCH
2
CH
2
NH
2
, OC
3
H
7
and the like.
The subject of the invention is more particularly a compound of the following peptide sequence:
Leu-Ser-Ala-Leu-Z (SEQ ID NO:3)
in which Z represents OH, NH
2
a substituted or unsubstituted hydrocarbyloxy residue, or a peptide sequence having from 1 to 10 amino acids, as well as the corresponding compounds in which the peptide bond is replaced by a bond resistant to the enzymatic degradation by proteases or in which the peptide backbone comprises one or more intercalated groups making the peptide bond resistant to enzymatic degradation.
The nature of the amino acids of Z is unimportant, the limit being that when modified amino acids are involved (not encoded genetically), these are not substituted by a bulky group (having a size greater than that of the radius of the iodine atom).
The compounds according to the invention comprise especially the peptides of the following sequence:
Ala-Leu;
Leu-Ser;
Ala-Leu-Ser;
Leu-Ser-Ala-Leu (SEQ ID NO:4);
Leu-Ser-Ala-Leu-OCH
3
(SEQ ID NO:4);
Leu-Ser-Ala-Leu-NH
2
(SEQ ID NO:4);
Leu-Ser-Ala-Leu-Gly-Gly-Gly-Tyr (
Fillion Gilles
Massot Olivier
Rouselle Jean-Claude
Institut Pasteur
Kemmerer Elizabeth
Muserlian Lucas and Mercanti
Wegert Sandra
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