FR2713645A1 - New rat and human melanocortin receptor MC-5 - Google Patents

Abstract

New polypeptides (I) having the activity of a melanocortin receptor, designated MC-5, are: (a) 325 amino acid polypeptide (Ia) (sequences for rat and human polypeptides reproduced); (b) peptides contg. (Ia); (c) fragments of (Ia); (d) peptides contg. the site(s) of (Ia) essential for binding to melanocortins and their synthetic (ant)agonists, or (e) peptides recognised by antibodies that recognise (Ia) but not the MC-1 to -4 receptors. Also new are (1) nucleic acid (II) encoding (I); (2) antibodies against (I); (5) nucleic acid probes that hybridise with (II), etc.

Description

The present invention relates to polypeptides having a

  melanocortin receptors, including adrenocorticotropic hormone (ACTH) and

melanotropic hormones (MSH).

  It also relates to nucleotide sequences, and in particular DNA sequences, encoding these polypeptides as well as to vectors containing said sequences and to cells transformed to express said sequences and in particular the genes coding for the receptors containing or consisting of by, said polypeptides, these cells making it possible to study the activity

  agonist or antagonist of said receptors.

  The invention also relates to nucleotide probes capable of being fixed by hybridization on said sequences or said genes coding for said polypeptides and intended for the diagnosis of affections resulting in a qualitative or quantitative modification of the formation or activity of said receptors, in humans or animals, and in particular cardiovascular, renal, neurological, psychiatric,

  gastroenterological or neuroendocrine.

  The invention also relates to monoclonal or polyclonal antibodies, human or non-human, directed against

said polypeptides.

  It also relates to screening means for drug candidates, in particular for studying the affinity of candidate substances for said polypeptides. Finally it relates to drugs, especially for the treatment of cardiovascular diseases,

  renal, psychiatric, neurological, gastrointestinal

  enterotoxic or neuro-endocrine, and containing substances having a high affinity for said polypeptides having melanocortin receptor activity or substances having an activity on cells transfected with said DNA sequences coding for

said polypeptides.

  It also relates to drugs that are active on one, some or all of the melanocortin receptors already identified and / or those described in the present invention and in particular to agonists or antagonists of the adrenocorticotropic and melanotropic hormones. The adrenocorticotropic hormone is a member of a family of opiomelanotropic peptides derived from a

  common precursor of high molecular weight, the

  opiomelanocortin (POMC). This precursor is hydrolyzed enzymatically to give ACTH, O-lipotropin (P-LPH) and an N-terminal part. These three peptides are themselves hydrolyzed, especially in the intermediate lobe of the pituitary, to give other active peptides. Thus the N-terminal region gives 7-MSH. ACTH is the source of α-melanotropic hormone (α-MSH) and intermediate lobe corticotropic peptide (CLIP). P-LPH can be hydrolysed to give β-endorphin and γ-LPH. These last two

  peptides are the source of 1-27-endorphin and R-MSH.

  The adult man does not have an intermediate lobe of the pituitary gland, so the plasma levels of a-MSH are very low. In addition, most of the i-LPH remains unchanged, so both R-LPH and ACTH are

  major melanocortins in humans.

  The biological activities of peptides derived from proopiomelanocortin are very varied. The primary role of α-MSH and f-MSH is to regulate the activity of melanocytes and thus pigmentation; ACTH and P-LPH

  also show powerful stimulants of pigmentation.

  The primary role of ACTH is to regulate the synthesis of glucocorticoids and aldosterone in the adrenal gland. Effects of ACTH have also been observed in various other cell types such as adipocytes, gland

lacrimal or lymphocytes.

  Melanocortins have many activities in the central or peripheral nervous system: regulation of CRH production in the hypothalamus (Motta et al., Endocrinology, 1965, 77: 392, Suda et al., Endocrinology, 1986, 118: 459), effects on

  avoidance behaviors (Murphy and Miller, J. Comp.

  Physiol. Psychol., 1955, 48: 47), and food intake (Sandmanet et al., Experientia, 1969, 25: 1001, Garrud et al., Physiol Psychol., 1974, 112: 109). These activities would not be induced indirectly by an elevation of cortisol, but due to the stimulation of

  brain receptors (Tatro, Brain Res., 1990, 536: 124-

132).

  The pharmacological study of the biological responses to melanocortins indicated that they may result from interaction with different receptors. Thus, some pharmacological data suggest that synthesis of glucocorticoids and aldosterone in the adrenal may be regulated by receptors with different affinities for α-MSH (Vinson et al., J.

Steroid Blochem., 1983, 19: 537).

  ACTH and MSH are known to interact with G protein-coupled receptors by activating adenylate cyclase. To date, four melanocortin receptors, called MC-1 to MC-4, have been cloned. The MC-1 receptor is an α-MSH receptor expressed in mouse melanocytes and human melanomas, but not in other tissues; the MC-2 receptor is an ACTH receptor expressed in the adrenal cortex (Mountjoy et al., Science, 1992, 257, 1248-1251) The MC-3 receptor, which has very similar affinities for short melanocortins ( MSH) and for ACTH, is expressed in the brain and placenta, but not in the adrenals or in melanoma cells (Gantz et al., J. Biol Chem., 1993, 268: 8246- 8250). The MC-4 receptor is mainly expressed in the brain but not in the adrenal, the

  placenta, nor melanocytes (Gantz et al., J. Biol.

Chem., 1993, 268: 15174-15179).

  The invention of the novel polypeptides above has made it possible to discover a new receptor for

  melanocortins which is hereinafter referred to as MC-5.

  The subject of the invention is novel polypeptides having MC-5 melanocortin receptor activity chosen from the group of polypeptides formed by groups 1 and 2 defined below: ## STR1 ## All of the polypeptides constituted by or containing the sequence of 325 Rat amino acids, defined in Sequence ID SEQ ID Ne! or peptide fragments of this sequence, said fragments being such that they contain the site or sites contained in said 325 amino acid sequence and whose presence is necessary for the fragment to be able to bind melanocortins or their synthetic derivatives, agonists or antagonists, or they are recognized by antibodies which also recognize said 325 amino acid sequence but which do not recognize any of the other MC-1, MC-2, MC-3 and MC-4 receptors, Set 2 of the polypeptides constituted by or containing the human sequence of 325 amino acids, defined in the SEQ ID NM 3 sequence identifier or peptide fragments of these polypeptides, said fragments being such that they contain the site or sites contained in said 325 amino acid sequence and of which presence is necessary for the fragment to be able to bind melanocortins or their synthetic agonist derivatives or ntagonists, or they are recognized by antibodies which also recognize said 325 amino acid sequence but which do not recognize any of the other receptors

MC-1, MC-2, MC-3 and MC-4.

  The invention also comprises the polypeptides constituted by or containing the sequences homologous to the sequences SEQ ID No. 1 and SEQ ID No.

  homology of at least 10% with said sequences.

  Preferably, the polypeptides of set 1 contain the sites belonging to said 325 amino acid sequence, the presence of which is necessary, when the polypeptides expressed by a cell are capable of increasing the accumulation of 3 'adenosyl, Cyclic monophosphate (cyclic AMP) when these polypeptides are placed in the presence of melanocortins or their synthetic agonist derivatives according to a pharmacology indicated in Table I. It can be seen in particular that the efficiency of α-MSH is equal to that of the Synthetic fragment 1-24 of ACTH, higher than norleu-Dphe a-MSH (NDP-aMSH) and ACTH (1-39) and much higher than those of other MSH while the

  ACTH fragment (4-10) is virtually inactive.

  The polypeptides according to the invention can be used by being isolated, or fixed on supports, in a quite conventional manner, or combined with amino acid sequences without connection with the MC-5 receptors. They can be glycosylated or not and

disulfide bridges.

  The subject of the present invention is also the nucleic acids containing or consisting of the nucleotide sequences coding for any of the polypeptides.

according to the invention.

  The nucleic acids according to the invention can

  understand or consist in the complete sequence, ie

  say the gene, encoding the MC-S receptor in humans or animals. Nucleic acids according to the invention are in particular nucleic acids comprising or consisting of the sequences SEQ ID N 1 or N 3 or fragments of these sequences. Among the nucleic acids according to the invention, particularly advantageous nucleic acids are those consisting of the sequences extending from the nucleotide at position 253 to that at position 1 227 in the identifier SEQ ID No. 1 and the nucleotide at position 184 to that in position 1158 in the identifier SEQ ID No. 3. The nucleic acids also include the fragments encoding the shorter polypeptides defined above. In addition to the nucleotide sequence variations that can be observed when passing from the rat DNA sequences to the human DNA represented on the identifiers SEQ ID N 1 and SEQ ID No. 3, the nucleic acids according to the invention may comprise the variations specific to the degeneracy of the code as well as localized mutations insofar as the variant nucleic acids hybridize with the probes capable of hybridizing, specifically, with the SEQ ID sequences

N '1 or SEQ ID N 3.

  The nucleic acids according to the invention can be obtained by conventional chemical synthesis of nucleic acid, by replication in vectors which contain them or by any other means, and in particular by multiplication by the so-called PCR method from a weak

  amount of nucleic acid according to the invention.

  The subject of the invention is also the recombinant vectors which can be used for cloning or for the expression of nucleic acids and which contain a nucleic acid according to the invention, such as plasmids, phages or viruses containing one or more sequences according to the invention. invention in a site not essential for replication. The vectors according to the invention may contain, if necessary, the elements necessary for the expression in a cellular host such as promoter, initiation codon, terminator, signal sequence or anchoring sequence or any

  another element useful for regulation.

  The subject of the invention is also the cellular hosts transformed with a recombinant vector according to the invention and capable of expressing the coding sequence according to the invention for the synthesis of a polypeptide according to the invention. These hosts may be prokaryotes, such as for example E. coli, or eukaryotes, for example yeast cells such as S. cerevisiae or cells

  mammalian, for example CHO cells.

  The subject of the invention is also the monoclonal or polyclonal antibodies directed against a polypeptide according to the invention. These monoclonal or polyclonal antibodies are obtained by induction from a polypeptide according to the invention and are specific for the polypeptides according to the invention, while being susceptible, or not, to

  recognize other melanocortin receptors.

  Obtaining these antibodies can be carried out in a conventional manner, either by injection of a polypeptide according to the invention into an organism and serum collection with optionally purification of the specific antibodies, or for the monoclonal antibodies, by the techniques

  conventional cell fusion forming hybridomas.

  The antibodies according to the invention are useful for the diagnosis, by antibody-antigen reaction demonstrated by means of a conventional revelation technique, for diagnosing pathological variations of cells expressing the MC-5 receptor. The subject of the invention is also the nucleotide probes hybridizing with one of the nucleic acids according to the invention or with their complementary sequences or corresponding RNAs, being specific for the MC-5 receptor, and which do not hybridize with the corresponding nucleic acid or RNA sequences of other

melanocortins described above.

  In a manner known per se, it is preferred that the probes comprise at least 10, and preferably at least 15

at 17 nucleic acids.

  The probes according to the invention are useful for the diagnosis of cardiovascular, renal, neurological, psychiatric, gastroenterological or neuroendocrine disorders related to qualitative or quantitative abnormalities of the MC-5 receptor, including for research.

  genetic anomalies at this level.

  The probes are conventionally used by being brought into contact, under the usual conditions, with preparations presenting nucleic acids of cells suspected of having an anomaly defined above. In particular, the probes can be used to detect pathological expression of the MC-5 receptor

  by revealing the presence of its messenger RNA.

  The probes corresponding to the complementary reverse sequence of the nucleic acids or of a fragment of these nucleic acids according to the invention, and constituted either of natural nucleic acids or of chemically modified nucleic acids provided that they hybridize with the sequence according to the invention can be used as antisense probes to block the expression of the MC-5 receptor. These antisense probes can be used as drugs in the treatment of cardiovascular and renal diseases, neurological and psychiatric disorders, gastroenterological disorders, including functional disorders of the intestine, motor disorders or secretaries

  and dysfunctions of the adrenal gland.

  The invention also relates to a method of screening drugs for the treatment of arterial hypertension and other cardiovascular diseases, neurological and psychiatric disorders, gastroenterological disorders, including functional disorders of the intestine, disorders motors or secretaries and adrenal dysfunctions. The screening of a drug may in particular use the detection of the ability of a melanocortin molecule or of a synthetic derivative to act as a ligand with respect to a polypeptide according to the invention, and consists, for example, in contacting, in a suitable medium, the melanocortin molecule or a synthetic derivative with the membranes of a cell host transformed with a vector comprising an insert coding for the polypeptide and capable of expressing said polypeptide so as to present on the surface membrane one or more specific sites of this polypeptide, such that the specific binding of the candidate ligand can be evaluated or indirectly estimated, for example by detecting the possible ligand-polypeptide complex. This method may also comprise the measurement of a response induced by the binding with the cell, such as, for example, the production of cyclic AMP so as to make it possible to differentiate the melanocortin molecules or their synthetic derivatives which act as antagonists and those which behave like agonists, and even define the

  relative character of the latter.

  For this purpose of screening, it is also possible to use a method determining the affinity of a polypeptide of the invention for specific ligands, in which a transformed cell host is cultured, in accordance with the invention, to express and present in its membrane the MC-5 receptor or a corresponding polypeptide, after which the cell culture is brought into contact with the determined ligand and it is verified whether a specific binding between the cellular hosts and the ligands is formed, in particular by radiolocation tests and preferably, measuring the rate of production or release of a suitable indicator such as cyclic AMP, or intracellular ions, the latter tests for distinguishing and defining the agonists and their partial nature and the antagonists. This method also makes it possible to determine the polypeptide fragments according to the invention, for example those comprising part of the sequences of 325 amino acids SEQ ID N 1 or 325 amino acids SEQ ID No. 3, and which comprise the operational sites allowing the binding and / or induction of the aforementioned cellular responses. It is also possible to identify cells or tissues expressing spontaneously on their membrane surface a polypeptide according to the invention, these cells or tissues then being usable for use in the development or screening of drugs or ligands interacting with the cells.

polypeptides according to the invention.

  The subject of the invention is also medicaments containing, in a dose to be administered, a therapeutically effective amount of an active substance, agonist or antagonist, on a polypeptide according to the invention having an MC-5 receptor activity in a

  pharmaceutically acceptable vehicle.

  The subject of the invention is also medicaments containing, in a pharmaceutically acceptable vehicle, an effective quantity of a substance which is active on other melanocortin receptors but which is not active on the

MC-5 receiver.

  Other advantages and features of

  the invention will appear on reading the description

  following, made by way of non-limiting example.

  In this description, the identifier of

  sequence SEQ ID No. 1 represents the sequence of a 1599 base pair DNA fragment of which 325 codons, identified on the sequence, coding for a 325 amino acid polypeptide constituting a melanocortin receptor

designated by MC-5.

  The sequence identifier SEQ ID No. 3 represents the sequence of a human DNA fragment of 1262 base pairs, including 325 codons identified on the sequence, coding for a polypeptide of 325 amino acids constituting

  an MC-5 receptor for melanocortins.

  Figure 1 illustrates the characterization of the transcripts of the MC-5 receptor gene in several tissues

of rat.

  Cloning of rat MC-5 and human MC-5 receptors 1. Cloning of rat MC-5 receptor A rat genomic DNA library was screened under low stringency conditions with a 32p-labeled DNA probe corresponding to a fragment of the nucleotide sequence encoding the dopamine D3 receptor (Sokoloff et al., Nature 1990, 347, 146-151). In these

  conditions, a clone hybridizes strongly with this probe.

  The nucleotide sequence of a DNA fragment (225 bp) of the phage thus isolated shows that this DNA comprises a sequence coding for a peptide of 75 amino acids encoding a protein having homologies with the family of

melanocortin receptors.

  The DNA fragment of this clone (nucleotide 810 at nucleotide 1038 of the sequence SEQ ID No. 1) is then labeled with 32P, and then used to screen a rat striatum cDNA library in the vector IZAP (Stratagene) in conditions of high stringency. A clone is then isolated and the plasmid is excised. The resulting plasmid (SLZ 82) is cultured, purified and then sequenced. The insert obtained (3 Kb) comprises the nucleotide sequence 1 to 1 599 of the sequence

SEQ ID N 1.

  2. Cloning of the human MC-5 receptor A genomic DNA library (Clontech) was screened under high stringency conditions with a 32p-labeled double-stranded DNA probe corresponding to nucleotides 812 to 1036 of the MC receptor nucleotide sequence. -5 rat (SEQ ID N 1). Two positive clones were purified and analyzed by the Southern technique and EcoRI-BamHI and Xba I restriction fragments were subcloned into pGEM-4Z (Promega) and sequenced. The sequence obtained (SEQ ID No. 3) has a homology of nearly 90% with the rat MC-5 receptor sequence while it is at most 64% with the other known melanocortin receptors. 3. Expression of Rat MC-5 Receptor in CHO Cells The coding portion of the rat MC-5 receptor was amplified by PCR using the nucleotide primers ACT CTT TTT CTT CCA GCG ATG AAC TCC (SEQ ID N 5) and GGA-TCC ACC TAA TTG ACT GAG AGA TGA (SEQ ID No. 6) using the SLZ 82 plasmid as a template according to the technique of Kawasaki et al. (PCR Technology, Erlich H.A., eds., Stockholm Press, 1989). The fragment obtained (1050 bp) is purified on agarose and then digested with Hind III enzymes.

and Bam HI.

  Expression vectors are derived from plasmid pSV D2 (Giros, B. et al., Nature 342, 923-926, 1989). The vector for expressing the MC-5 receptor is obtained by replacing the HindIII-BglII restriction fragment of pSVD2 with a HindIII-BamHI restriction fragment obtained above, leading to the plasmid pSV MC-5. These constructs are cultured, then purified on a cesium chloride gradient (Sambrook J. et al., Molecular cloning - a laboratory manual, C.Nolan, ed., Cold Spring Harbor Laboratory Press, 1989) and transfected (Graham, FL and al., Virol., 52, 456-467, 1973) to Chinese hamster ovary cells (CHO-K1) deficient in dihydrofolate reductase. Stable transfectants are selected in a culture medium (Dubelcco's Modified Eagle medium) without hypoxanthine

and without thymidine.

  The expression of the MC-5 receptor is demonstrated by the binding of NDP-rMSH [tyr-125I] (Tatro and Reichlin, Endocrinology, 1987, 121: 1900) to transfected cell membranes. The binding experiments are carried out in a 50 mM Tris-HCl buffer pH 7.4 (total volume 400 μl) containing 120 mM NaCl, 5 mM KCl, 2 mM MgCl 2, 2 mM CaCl 2 and NDP-c MSH [tyr-125I] to a concentration of

0.1 to 0.2 nM.

  Expression of the MC-5 receptor in transfected CHO cells is also evidenced by the ability of melanocortins to stimulate cyclic AMP accumulation in these cells. To measure the cyclic AMP accumulation, the transfected CHO cells are cultured on 96-well plates, washed in Eagle-modified Dulbecco medium (DMEM, Gibco BRL) and then placed in the presence of a melanocortin or a synthetic derivative. for 15 minutes at 37 ° C. The cyclic AMP is extracted and quantified by radioimmunological assay (New England Nuclear). Melanocortins induce a cyclic AMP accumulation of 4-5 times the basal value measured in the absence of melanocortin. This measurement makes it possible to determine the agonist nature of melanocortins for the MC-5 receptor and the efficacy of melanocortins or of their synthetic derivatives according to Table I.

TABLE I

  Efficacy of melanocortins and their synthetic derivatives to stimulate cyclic AMP accumulation in CHO cells expressing rat MC-5 receptor AGENT EC50 (nMN)

ACTH (1-24) 0.46

a-MSH 0.59 NDP-a-MSH 1.0

ACTH (1-39) 6.0

  Table I clearly indicates that the gene transfected into CHO cells encodes a melanocortin receptor as indicated by the high efficiency of α-MSH and ACTH and their NDP derivatives. - cMSH and ACTH (1-24). However, the pharmacology of this MC-5 receptor can in no way be confused with that of

  melanocortin receptors already known.

  Characterization of MC-5 Receptor Gene Transcripts in Several Rat Tissues Poly (A) + RNAs are prepared from several rat brain or peripheral tissues (Chirgwin et al., Biochemistry 18, 5294-5299, 1979; et al., Proc Natl Acad Sci., 69, 1408-1412, 1972). Samples (8 μg) were denatured, electrophoresed on agarose, transferred to nitrocellulose membranes and hybridized using a 225 bp fragment (nucleotides 810 to 1038 of the sequence SEQ ID No. 1) obtained by amplification of DNA from using oligonucleotide primers,

  then marked at 32p by the technique of "nick-translation".

  This labeled fragment is used at a rate of 5 x 106 dpm / ml. The membranes are exposed for 15 days at -80 ° C. with amplifying screens. In rats, a transcript (4.0 kb) is observable in the adrenal and stomach (Figure 1). The expression of the transcripts of the MC-5 receptor in the rat brain has also been studied by the PCR technique. Monobrin cDNA was synthesized using AMV reverse transcriptase (20 U, Boehringer), RNA prepared by Chirgwin et al. (Biochemistry, 1979, 18: 5294) and primer A: 5'-CAT GAT CAT TAG GAT AAG GTG AAG (SEQ ID NO: 7) (400 mM). This matrix is then amplified (Kawasaki et al., "PCR technology", Erlich HA ed., Stockholm Press, 1989) using primer A and the 5'-ATC primer GAT CGT CTG CAT CAT CTC CTC (SEQ ID N 8) (75 mM each) for 35 cycles as follows (94 C, 1 minute and 72 C, 1 minute) with 5 U Taq DNA polymerase (Perkin Elmer Cetus). A DNA band of predicted size of 225 bp is visualized with ethydium bromide and its identity with a fragment of the MC-5 receptor is determined by hybridization with a probe consisting of a mixture of oligonucleotides -TCT GAC ATG GTT CCG GGC CA (SEQ ID NO: 9) and 5'-CAG CAT GAA GGG TGC TAT (SEQ ID NO: 10) labeled at 32p by the

terminal transferase.

  Expression of transcripts was also studied by in situ hybridization using a cRNA probe. To synthesize the RNA probe, plasmid pGEM-4Z containing the fragment comprising the sequence SEQ ID No. 1 was used between nucleotides 812 to 1036. To obtain the antisense cRNA probe, the plasmid was linearized with EcoRI and this template was used in the kit "Riboprobe 'GemIni II" (Promega) with T7 RNA polymerase and UTP 32P. To obtain the sense cRNA probe, the plasmid was linearized with Hind III and used with SP6 RNA polymerase. These probes were hybridized to rat adrenal sections according to the technique described by Bouthenet et al. (Brain Res., 1991, 564: 203). In the adrenal, the MC-5 receptor is only expressed in the glomerular layer, the site of synthesis of aldosterosis. The MC-2 receptor is expressed in the fascicular layer, the site of synthesis of glucocorticoids and, to a lesser extent, in the glomerular layer (Mountjoy et al.

coll., Science, 1992, 257: 1248).

19 2713645

I, TSTE OF SEQUENCES

  (l) GENERAL INFORMATION, E: (i) DEPOSITOR:

  (A) NAME: NATIONAL INSTITUTE FOR HEALTH AND

MEDICAI RESEARCH, E

(B) STREET: 101 Tolbiar street:

(C) CITY: PARIS CEDEX 13

(E) COUNTRY: FRANCE

(F) POSTAI CODE: L 75654 (ii) TITLE OF THE INVENTION: Polypel

  melanocortins, medicamemits comprising them, seq uences encoding potiur them, q.dfles, vectors and hlites expressing

  and application to drug screening.

  (] ii) NUMBER OF SEQUENCES: 10 (iv) LISIBILY FORM BY COMPUTER: (A) TYPE OF SUPPORT: Floppy disk (B) COMPUTER: IBM PC rompatil) ble

  (C) EXPI SYSTEM, OITATION: PC-DOS / MS-DOS

  (D) SOFTWARE: PatentIn Release # 1.0, Version # 1.25 (EPO) (2) INFORMATION FOR I, A SEQ ID NO: 1: (i) CHARACTERISTICS OF THE SEQUENCE: (A) ILONGUEUR: 1599 base pairs (B) TYPE: nucleated acid (C) NUMBER OF STRANDS: double (D) CONFIGURATION: linear (ii) TYPE OF MOLECULE: cDNA (iii) HYPOTHETIQIJE: NO (iii) ANTI-SENS: NO (vi) ORIGIN: ( A) ORGANISM: SP (, lelîlr'.f inleo) i] dlique titr (el) ttlr MC-5 d (the rat (ix) CHARACTERISTIC ADDITIONEILE:

(A) NOI / KEY: CDS

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  Z16 9DD V1V DDD 5WVV Dl9 IVD DVV 9DDD DDD9 1JD D1D DDIV DVD VIV iVI 0T ooZ 561 061 na'IaS 1 eA aWH aLld aLtid na'll ll: aqd aqd aH.as ai nalI sA SAD 98 DID IDI D1E 1IV Dl DIl DLD 91DV DDV D11 Dl 91V DDI DIV DID D91 S81 08l SLI LEA ali leA tAI sA'I -AiS IID EaL JAu A ali ai ali l ai al) sAD 918 D1) D DJ1V D1); VL VV DDL VVU VI D1V D1V D11 J9D D1V IDE D91 OLI.9l 091 aS a [I sAD a4d - "11 dl 4l alI SAD VIV ai aI [eA A JE) iaS b'V b1V 89L DDV V.IV DJ 11i DDV 991 D1V D91i DD9 DIV 1IV úif 999 DDI DDD 9DV SP9ET ZZ I z

SLI OLI S91

  AID sAD -as alI sAJD ald aJI. dzú al sAD eiV ail alI leA 091 551 051 5iv1 0ú AID ias FiV b.IV V -1t4 laiH alI SIH S! H iAI b V nl'I elv lAI a4d Okl SûI 0 [ali tlj alI iAI D2V dsV leA elV alI ely Na'i na SAD jaH * as ZI OZI 5it 11 1> 11 S ualV IaA 1a laa a1l1 sAD a 1 lH iW s dsV ati dsV ati dsV alI S! H SZ 011 oul 001 bV 1LA aliid 2.I. (IsV L1V a1l ULA ILA s! H SqI usv usv alI naI -.A.t

56 06 58

  aIl aqj alI It.l iD dil 2 [V uSV.aS lOa] i las! eA noq: aH dsV PIV

08 SL OL S9 OZ

  the AiV na'I laoS AID leA aql ad al AI H d zaW s.lH rfa'I uSV sAI

09 OS 0S

  USING THEM ALIYELY HAS ALONE ALLIED TO HIMSELF THROUGH HIMSELF HIMSELF HAS NEITHER HAS ALLEGEDLY HELPED THE NORTHERN HUMAN RIGHTS COUNTRIES 9z 0 z òelV * aS as usIv usIv 1LA usV ul AID naq alI usV dsV nlID iaS SI Ul SI e [V usV na'l J.qJ, Itaq dsV nial 1, 'ltlJ naq sti tas la us usV O: Z: ON (i) 3S: ODlnifaS V'I sG NOIldIBDSS3 ((! X) 0l al! ôOl ds3'IfD3l'IOw sa ad I (1!) d -1 LUt! I [: NOI.LVfDIaI ## EQU1 ## Z)

  6651 1D DDIIDD9. DI D.II.D19.111 DD991DVIIV DDVIIVIVID DDD9DD919D9D

  LFSI DDVVVDV / VVED 1IVDI.DI'DDDV D. [DDD.DDUD DVVUVDEDUVD V / DDVIUTDD9D 19DVVID9DD L8ffl OVDIlDDI.DDI IVDDVDIII, D9VV. ú.L) DD1.9VDDD DDID1DIDDLD VDIDDIODD

9V9úT.Z:

  Phlie Island Tyr Island Tyr Glu Ser Lys Tyt Val Tle V.l Cys I.eu Island Ser 185 19n Plays Plie Tlr Met Leu Phie Ple MePt Val Ser I, had Tyr the His Met

200,205

  Plie Leu Leu Ala Arg Asn flis Vl I, ys A'q Ala Ala Ser Pro Arq

210 215 220

  Tyr Asn Ser Val Arq Gin Arcq Ala Ser Mel Lys Gly Ala Island Thr Leu

225 230 215 240

  Thr Met Ieu Leu Gly Island Phe Island Val Cys Trp Pro Ser Plie Pbh, eu

245 250 255

  His Leu Ile Leu Met Island Ser Cys Pio Cmii Asn Val Tyr Cys Ala Cys

260,265,270

  Plie Met Setr Tyr Plie Asn Met Tyr: T, eu Tlie Lel Ile Met Cys Asn Set

275 280 285

  Val Island Asp Pro I, had Ile Tyr Ala place Arq er Gin Glu Met Arq Arq 290 295 30On Tlr Phe Lys Glu Island Ile Cys Cys Hlis Gly Pie Arq Aig Thr Cys Tbr

305 310 315 320

Leu Leu Gly Arq Tyr

325

  (2) INFORMATION FOR SEQ ID NO: 3:

  (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 1262 par: e: s the base (B) TYPE: ntucléi acid (liUe (C) NUMBER OF STRANDS: double (D) CONFIGURATION: linear (ii) TYPE OF MOLECULE : CDNA (iii) HYPOTHETIQTY: NO (iii) ANTI-SENSES: NO (vi) ORIGIN: (a) ORGANISM: Nominal sequence of receptor MC-5 huma in 0l 5t [0 EI JlqZ lea.XAu blV dsV lea elyoi a ly nThe nI'I Aleos SAD eah ELV Z19 DDV D1D DV1 DDV 1VD 919 VDL) 11V DDD D1D VII DDV DDL D1V 3DD VD9 z1 ozi JII Lea CAEL m S 1I SAD garlic 1H { "S DISV ATID Lea usv dsv Ali 9RH b 0V t9s 91DE) DiD DI 1lVD DD1 2) V D1V 3DJ1 DVD ú.11 919 úV DV1 1lV DVD DD3 ULi SOi 00l leA ticd iel (SV elV all leA kaOl Sill sAql usv usr nrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrr VED9 VLV 9ID9 V1D J; VD 9VV DVV DYV 3D3D V1D DV1 D1V

S6 06 58 08 5Z

  liii ú11 1 l t D dl: lAS.lS 1aN; l1S iLA ia'iW dsy elV eA

  89V 3DV D1V DDV 9VD 991 DDD 19V D3.1 DIV DDV 919 D1D D11 DVD DDD D1D

  SiL UL 59 elkV r'l iS SAD 1 j alqd ald iAjI: laW Od aS SH ria'l usV sAl tiusV O0Z VDD D1D DDV DD1 D1D DAl DVI 'DV DDD DD1 DVD 1DD DVV 1VV DW oz 09 bb OS S '' Aili elv AiA [11 the AIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIII

  ZLE 01VV D19D VIV DDD D009 V1V D1D D11 D1V DVV 9V 911. D1D D9V DIV D19 3

  SV U U U E U U D E D D D D D D IV D IV DDD DIV D0D VY9 191 V3DD Os', OZ to 9sA'I usVi sA'l lla UsV ('d A1 -las na'l U9sV Ai [n19.111e [1V 9LZ VD1J .DVVVVVV D19D IVV' Di V1D VDI IID DVV D99 9V9 VDV DD9 s51 I 01 O USV r-, 'l1 USy nIal (ISV hI ai [ds ll H aq s! H HHHH WKH DZLQJ DQG DQG DQG DQG DQG DQG DQG DV \ D 11 VDI DDI I VV D1V VD9 081 VDDIDIIIVI 0D1DVUVDV 9VVDDDlDD1 liVVV 319VDV 111191VDVV VVIIIVVDD919 oz [11 VD91111i D3DVV1DDtDIDE 99IDlllDL llDIDDD9 D91VIDD9VID1 19Di19191DJ 09 DDD9DYIlDI IDDDD31VDI iY191911DVD 91VDlDLDú DD1 9VDDD9D9V 91YDIDV9V SE: oN 1 (i US; iMîMfI.S V'L 21G NOI1dlaDS ' 4 (iX) 211 '-' {B [:. LN3H2DVqdWH (S) Sui: 'ID / HO N (V)

  3'I [: NUEII. IG (I / -41 1 $ IúSITVD (XI)

0lú dsv biV biv Old oaqd as S

  8811 2IDLD9919D LDLDDLDDLD VVVDVD9VVI 1V9 99V VV DDD ILI D9DV

  Sl1E OIE SOc SAD elV a8l btV atld AI9 bI. V sAD sAD ali al [nid sAl arld.iLq sAq Otil 1DDL DDD DIV DDV DJI 199D D19D DDL DDI IUV IIV 9V9 DVV 11I DDV DVV

OOE 56Z 06Z

  biV jaH ni9 ulId iQ iAZ elv JAL ali naq Oid dsV l & H leA aS Z601 99DDD DiV OV9 VVD D9V DDj DVI DDU9 JI VIV LDD DV9 DIV 919 DDI

S8Z 08Z SLZ

  usV sAD 1aH alI Ia'1 al! nfij IA aI usV bt lI d is! H las 11W arid bJV

  M01 IVV L91 D9V DIV DID VIV DID DV1I 9V IVV DVD D1L IDI 9LV DLI D9D 5Z

  OLZ 59z 09Z las sAD AI nal usV Ul9 Old SAD JaS naq Wa1 na'I ql1 nal SIH nal 966 1DL DDL DVI DID DVV DVD IDD D9L IDI IID 91V IDV DID IVD IID aiid a ld OJd e [V di sAD leA - $ lI alId leA A [9 1 a 'naq law qu jeA OZ 8k6 DU1 Dl 9DD2 DD DD DD91 919Du DV Ili 919 D9D 91DD 91D DIV DDV D19

SEZ OEZ SZZ

  ati A UHV AID UlD UO aaS - iq biv ulD bJv eiV -as as elV A1D 006 DDV D 19DDD DD9D D 9D DIV DDV DDV uD 9VDD 9D DDD9 D1 DD9V DDD DD999 OZZ SlZ 0UZ ST oId aI elV elV alI bV sAI the A S! H -il b'V 1V nal na'ia a4d IaW ZS8 DDD DID ID DDD 9D9 1V DD99D V DV Dt DVD IDV DD DDD9 9DD D1D DII DIV SO SO UOZ 561 slH garlic úAI naIl AaS leA nIl b 'He atld the 'I lW elV alid atld lai las 1'08 DVD VIV DVI DID 91D 91D2 ID 91l DIV ID29 Dl D21 9LV DD1 OT 06l SBi 081 BiI naq SAD 11'l alII leA lAI "Itl' aS nli9 I aS lAI nag ali at ld the 9SL VDIY D2ID DD91 9D D1V DVI DDV DDL VVD VDI DVI D9D D12 DLI D2 9

SLI OLI 591 091

  IIA AiD SAD AD9 AQL sA2 alid ELV d.il * It A19 ELV II Ali eV ID B0L LLV DD99 DD91 DD9D 9DV D91 Dl DD DI D1V D99 DD9 DLV DIV DDD9 999,551,051 Sti JaS bDJV b [V e thy IV it lal al 1 s! H l AI e [V naq 81V JAI atld alI 099 VDI DD9D 99V DDD DDV 91DV DIV DVD DYD DV DD DD DD9 DVI DII DIV 979u TZ zs / I OLI cJ91 leA ali AID SAD AID 1t. L. sAD aild IV diAl AID elV ali al elv 091 SSI 0oSI St AID JaS b.zV bV elV A14.1 aW all S! H SIH IAu ely na'l elVI JA.L atd 0t1 SEI 0EoI alI LUL leA.AL biv d9v leA elV ali elV nl ina'I laS sAD IaH iaS SZl UZui 51Sil Z UlV leA le JUS alI sA;, laIH las (sV aEld lea LIvs CISV B} I SFH

011 SUI 001

  bl the ad elV ds el a (all leA naLlSHilS usV USV I'a 'na'I 21A.

56 06 58

  ai i. * 1I ali til. ngid dl, elV {aS las aH.l2aS leNal laW dsV elV oZ

08 SL UL 59

  SAD [IAEA SAD [IAAIDOIDIDAL ALLOW S HILDREN 'S HEREIN THE CA N' ALI USV NICHI 'I nlaI lai ali sv ot v E SlT ea AID na, l -lq. naql ald ILA nlD lea el ali aID laW disV nl SAD

  O1d JaS -aS sA'I usv sA 'ls TJsV Oid AI9 iaaS Inaq tIsV AID nl [D atlj.

  If it is not possible to use it at all, it is important to use it as a tool. aDNa213nS V ': 4 (1 NOI.dIDSSaU (! x) k "u lt)? {; *; 31' D: JI3'lIUW 3C; dAl, (!!) ai.water! [: NOIiVSi9IDINO3 (L]) as follows: - 'qdAL (') s auiule sap! ie SZE Hi] 3lilDNO'I (V): 13DN3 {llas V'I his (S3nllúSIa3l. DZavD (!) :: oUl (I11 aS V ' I afOd NOItVH1OINI (Z)

Z9Z.IL LVDDIVDDVI

  8tZ1 DDIDVDDDVI 9DDV199DDDDVVDVDVDVDDVVVDUVDID DVDD, 11TD.1.DDD.L.1D

V9ú'TZZ

  9Z a'ub! 91a: mau apD! From: 3dAL (ifd) Saspq to [sa! Edl 6Z: uin3n9DNOI (V): aDNaflC3S V'I to SanItSIasi3.DVaVD (1): 9: ON aU1 QS V'I aflOd NOIlvW / HOANI () 0ú

  6Z DDLDVV9LV DJD9DDVUD.L.DI I1. .DVVLD

  : - ON it 03S: a.DN3flOS V'i 3C NOIldIDS3aq (lx) (IawuiJd) asa3ilItAs ap apljojaOnuobilo: a'lnD3'IO 3a 3dAl (.!) L! ## EQU1 ## where: ## STR1 ## :: ddAl (8) sasL (I al Sc! eE L 6Z:) u [IQu1NO'I (V): 3DNM [IC3MS V'l 3a SMfIISI213LDVHVD (!) :: oN G (1 S V'I aflOd NiOIIHVaUONI ( Z) SZú Oz lISV Db.V t) IV O-ld aLld UcE 51L 01 [[SOY als sAD V! Y all biv alid AD bti.v sAD sAD o all idf SA'I aqitd] qj oo00 6Z 06Z SA ' I bIV iaW Illb uID -19 JV IJAI el / V-AL oI l I l l l l d iSV laW [THE eA s5z U8c bLZ IJS USV sAD lWH atl Io.l 'd itb'l AI laH UsV atid SIH JS 1WH at Id OLZ.9z 09Z bIli) S SAD; ## STR1 ## where: ## STR1 ## wherein the above is shown in FIGS. I A 11 [[[[[[[[[[- - - - - - - - - - - - - - - - - - - - - - - - y el'V -aS laS '1y

O0f. SIZ 01Z

  AI19 - ldl'l ejV LIV all b {1 SiA 'ItA S [! H -'liL [) AV elev lal na'I a id S0z OUO 561 laW 9IH all.IA.L Ila'1] 1S leaA' 1 .l1l1l1l1l1l1l1l1l1l1l1l1l1l1l1l1l1l1l1l1l1l1l1l1l1l1l1l1l1l1l1l1l1l1l1l1l1l1l1l1l1l1l1l1l1l1l1l1l1l1l1l1l1l1l1l1l1l1l1l1l1l1l1l1l1l1l1l1l1l1l1l1l1l1l1l1l1l1l1l1l1l1l1l1l1l1l1l1l1l1l1l1l1l1l1l1l1l1l1l1l1l1l1l1l1l1l1l1l1l1l1l1l1l1l1l1l1l1l1l1l1l1l1l1l1l1l1l1l1l1l1 '

GV9ETZZ

  LZ7 (C) NUMBER OF RRTlqS: simpl1c (D) CONFIGURATION: lin,;, ire (ii) TYPE OF ME, ECTILE: O liqoiu16l synthesis (primer)

  (xi) IA SEQUENICITY DESCRIPTION: SEQ ID NO: 6:

CTGGATCCAC CTAATTGACT GAGAGATGA 29

  (2) INFORMATION FOR SEQ ID NO: 7:

  (i) CHARACTERISTICS OF THE SEQIJUENCE: (A) LENGTH: 24 pairs of bases (B) TYPE: Nuicylic acid (C) NUMBER OF STRANDS: single (D) CONFIGURATION: linear (ii) TYPE OF MOLECULE: Synthetic oligonucleotide (prim .er)

  (xi) DESCRIPTION OF THE SEQ IDEN: F. SEQ ID NO: 7:

CATGATCATT AGGATAAGGT GAAG 24

  (2) INFORMATION FOR I, A SEQ ID 110: 8:

  (i) CHARACTERISTICS OF SEQI1ENCE: (A) LONGUEIlR: 24 pairs (hasps (B) TYPE: nileicuie acid (C) NUMBER OF STRANDS: single (D) CONFIGURATION: I ileaire (ii) TYPE OF MEIECIJ, E: O iqontlcieot ide e synthesis (primer)

  (xi) DESCRIPTION OF THE SEQUENCF .: SEQ ID NO: 8:

ATCGATCGTC TGCCTCATCT CCAT 24

  (2) INFORMATION FOR I, A SEQ ID NO: 9:

  (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 20 p) units of bars_s (B) TYPE: nucleic acid (C) NUMBER OF STRANDS: single (D) CONFIGURATION: lii.neaire (ii) TYPE OF MOIECULE : I l (: ynth ynth ynth st st st st 01 01 01 01 01 01 01 01 01 01 01 01 01 01 01 01 01 01 01 01 01 01 01 01 01 01 01 01 01 01 01 01 01 01 01 (! ## EQU1 ##. ## EQU1 ##. ## EQU1 ##. ## STR1 ## (A) [L: .e: 3dkL (fi) sisesI 'D s.! E, 81: HI-IL'llINO'I (Y):' DNu: .ill'S V ## STR1 ## : RN a1 03S: dDDINIU.l ''S MVA sGa NOILdIdDS2 (! X) 6Z

Claims (20)

  1. New polypeptides having an MC-5 melanocortin receptor activity chosen from the group of polypeptides formed by the sets 1 and 2 defined below: all of the polypeptides consisting of or containing the 325 amino acid sequence of a rat, defined in the sequence identifier SEQ ID No. 1 or peptide fragments of this sequence, said fragments being such that they either contain the site or sites contained in said 325 amino acid sequence and whose presence is necessary for the fragment to be capable of binding melanocortins or their synthetic derivatives, agonists or antagonists, or they are recognized by antibodies which also recognize said 325 amino acid sequence but which do not recognize any of the other MC-1, MC-2, MC-3 and MC-4, Set 2 of polypeptides consisting of or containing the human sequence of 325 amino acids, defined in the sequence identifier this SEQ ID No. 3 or peptide fragments of these polypeptides, said fragments being such that they 25 either contain the site or sites contained in said 325 amino acid sequence and whose presence is necessary for the fragment to be able to bind the melanocortins or their synthetic derivatives agonists or antagonists, 30. or they are recognized by antibodies which also recognize said 325 amino acid sequence but which do not recognize any of the other receptors MC-1, MC-2, MC-3 and MC-4.   2. Polypeptides of the assembly 1 of claim 1, characterized in that they contain the sites forming part of said 325 amino acid sequence, the presence of which is necessary, when the polypeptides are expressed by a cell, in particular CHO, in the presence of melanocortins or their synthetic agonist derivatives so that the efficacy of said agonists corresponds to that indicated below: AGENT EC50 (nM) ACTH (1-24) 0.46 a-MSH 0.59 NDP-u-MSH 1.0 ACTH (1-39) 6.0 P-MSH 12   v-MSH 46 3. Nucleic acids containing or consisting of the nucleotide sequences encoding any of the   polypeptides according to claim 1.   4. Nucleic acids consisting of or comprising the complete sequence encoding the MC-5 receptor in man or in animals.   5. Nucleic acids comprising or consisting of the sequences SEQ ID N 1 or N 3 or fragments of these sequences. 6. A nucleic acid according to claim 5 consisting of the sequence extending from the nucleotide at position 253 to that at position 1227 in the identifier. SEQ ID N 1.   Nucleic acids according to claim 5 consisting of the sequence extending from the nucleotide at position 184 to that at position 1,158 in the identifier SEQ ID N 3.   8. Recombinant vectors for use in cloning or expressing nucleic acids, and   containing a nucleic acid according to one of the claims 3 to 7.   Cell hosts transformed with a recombinant vector according to claim 8 and capable of expressing the coding sequence for the synthesis of a   polypeptide according to one of claims 1 and 2.   10. Monoclonal or polyclonal antibodies directed   against a polypeptide according to one of claims 1 and 2.   11. Nucleotide probes hybridizing with one   nucleic acids according to one of claims 3 to 7   or with their corresponding complementary sequences or RNA, being specific for the MC-5 receptor, and which do not hybridize with the nucleic   Corresponding RNAs from other melanocortin receptors.   12. Probes according to claim 11 for the diagnosis of cardiovascular, renal, neurological, psychiatric, gastroenterological or neuroendocrine disorders related to qualitative anomalies or quantitatively the MC-5 receptor.   13. Antisense probes comprising or consisting of the complementary reverse sequence or a fragment of the acids   nucleic acid according to one of claims 3 to 7 and   hybridizing with one of said nucleic acids, for   block the expression of the MC-5 receptor.   14. Probes according to claim 13 for the treatment of cardiovascular, renal, neurological, psychiatric and gastroenterological disorders, in particular functional disorders of the intestine, motor or secretory disorders and dysfunctional disorders. the adrenal.   15. A method of screening drugs for the treatment of cardiovascular diseases, in particular arterial hypertension, neurological and psychiatric disorders, gastroenterological disorders, in particular functional disorders of the intestine, motor or secretory disorders, and adrenal dysfunctions. in which a candidate molecule is contacted in a suitable medium with the membranes of a cell host transformed with a vector comprising an insert coding for a polypeptide according to one of the   claims 1 and 2 and capable of expressing said   polypeptide so as to present on the membrane surface specific sites of this polypeptide, the possible complex   ligand-polypeptide that is formed then being detected.   16. A method for screening medicaments for the treatment of cardiovascular diseases, in particular arterial hypertension, neurological and psychiatric disorders, gastroenterological disorders, in particular functional bowel disorders, motor or secretory disorders, and dysfunctional disorders. adrenal system in which a response induced by the binding of a candidate molecule to a cell, transformed by a vector comprising an insert coding for   a polypeptide according to one of claims 1 and 2 and   capable of expressing said polypeptide so as to present at the menbranar surface one or more specific sites of this polypeptide in such a way that the measurement of a signal such as the production of cyclic AMP makes it possible to differentiate the melanocortin molecules or their synthetic derivatives who behave as antagonists and those who who behave as agonists.   17. A method for screening labeled ligands such as radioactive or fluorescent ligands in which the specific binding of candidate ligands to the membrane of a cell transformed with a vector comprising an insert coding for a polypeptide according to one of the following is measured.   claims 1 and 2 and capable of expressing said   polypeptide so as to express at the membrane surface one or more specific sites of that polypeptide in such a way that the specific binding of the candidate ligand can   be evaluated or indirectly estimated.   18. A method of identifying tissues or cells expressing spontaneously on their membrane surface a   polypeptide according to one of claims 1 and 2 of such   tissue or cell, can be used for the development of drugs or ligands labeled according to claims 15 to 17.   19. Drugs containing, in a dose to be administered, a therapeutically effective amount of an agonist or antagonist active substance, on a polypeptide having MC-5 receptor activity in a   pharmaceutically acceptable vehicle.   20. Drugs containing, in a pharmaceutically acceptable vehicle, an effective amount of an active substance on other melanocortin receptors   but not active on the MC-5 receiver.