Neuropeptide Y agonists

Details Neuropeptide Y agonists Neuropeptide Y agonists

2000-08-18

2004-02-24

Kunz, Gary (Department: 1647)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Peptide containing doai

C514S004300, C514S011400, C514S012200, C530S300000, C530S317000, C530S321000, C530S324000

Reexamination Certificate

active

06696409

ABSTRACT:

FIELD OF INVENTION
The present invention relates to peptides which mimic certain of the biological activities of Neuropeptide Tyrosine (NPY) at specific NPY receptors that modulate neuronal release of physiologically active substances. These receptors are often located on neurones at neuroeffector junctions and, in some tissues and species, have been classified as of the NPY Y2 receptor subtype. In addition, the present invention relates to pharmaceutical compositions including, as the active ingredient, these peptides and to methods of treatment involving the administration of these compositions.
BACKGROUND OF INVENTION
Neuropeptide Y, a 36 amino acid peptide belonging to the pancreatic polypeptide family, was first isolated from porcine brain in 1982 (Tatemoto et al., 1982) and has since been identified in most sympathetic postganglionic neurons innervating the cardiovascular system, where it is co-localised with noradrenaline (Potter, 1988). In the cardiovascular system it raises blood pressure by an action on postjunctional neuropeptide Y receptors (Dahl{overscore (o)}ff et al., 1985; Potter, 1985; Revington et al., 1987; Potter and McCloskey, 1992) and inhibits neurotransmitter release—both acetylcholine (Revington et al., 1987; Warner and Levy, 1989) and noradrenaline (Edvinsson, 1988)—by acting on prejunctional neuropeptide Y receptors. Receptors for neuropeptide Y are also located on sensory nerve terminals and their activation can modulate local neurogenic responses (Grundemar et al., 1990;1993). These two receptor subtypes have been called neuropeptide Y Y
1
(postjunctional) and neuropeptide Y Y2 (prejunctional) on the basis of the different responses to a truncated analog of the related peptide YY-(13-36), when compared with neuropeptide Y in in vitro assay systems (Wahlestedt et al., 1986). Apart from these historically well-defined neuropeptide Y receptors the existence of a number of other subtypes (Y3, Y4, Y5, Y6 and Y7) have been suggested on pharmacological grounds and details of the cloning of receptors corresponding to Y1, Y2, Y4 and Y5 have been published (Herzog et al., 1992; Gerald et al., 1995; Bard et al., 1995; Gerald et al., 1996). The distribution and physiological significance of these various receptor subtypes has yet to be defined. Although some controversy has existed about the selectivity of truncated forms of neuropeptide Y for one or other receptor subtype (Potter et al., 1989), the emerging picture supports the initial classification into pre- and postjunctional receptor subtypes. Cell lines have been developed which express one or other neuropeptide Y receptor subtype and the development of receptor-selective analogs of neuropeptide Y has focussed mainly on binding characteristics in these cell lines (Sheikh et al., 1989; Aakerlund et al., 1990; Fuhlendorff et al., 1990). More recently, a cDNA encoding the neuropeptide Y Y
1
receptor has been cloned and cell lines expressing the cloned receptor have been analysed for both specific binding of neuropeptide Y analogs (Herzog et al., 1992) and functional responses elicited by specific analogs. From such binding studies, combined with subsequent studies in vivo, two analogs have been classified as acting specifically on the postjunctional (neuropeptide Y Y
1
) receptor. These neuropeptide Y Y
1
selective analogs, (Pro
34
) neuropeptide Y and (Leu
31
, Pro
34
) neuropeptide Y, mimic the action of neuropeptide Y in raising blood pressure, and also share similar binding to cell lines expressing only neuropeptide Y Y
1
receptors e.g. the human neuroblastoma cell line SK-N-MC and fibroblast lines expressing the cloned neuropeptide Y Y
1
receptor (Herzog et al., 1992). Neither exhibits the neuropeptide Y Y
2
receptor action of inhibiting cardiac vagal action in vivo, a manifestation of inhibition of acetylcholine release (Potter et al., 1991; Potter and McCloskey, 1992).
Activation of neuronal prejunctional NPY receptors generally inhibits nerve activity, reducing the release of neurotransmitters in response to nerve impulses and in response to local factors acting to release neurotransmitters (Wahlestedt et al., 1986).
NPY-containing neurons are evident in the nasal mucosa of various species including man, often associated with glandular acini and blood vessels (Baraniuk et. Al., 1990; Grunditz et. al., 1994). Stimulation of the parasympathetic nerve supply to the nasal mucosa (vidian nerve) in dogs increases blood flow in the region and the major part of this effect is atropine resistant. Intravenous administration of NPY reduces vasodilitation due to parasympathetic nerve stimulation, an effect that was not mimicked by the NPY Y1-selective agonist [Leu31, Pro34]NPY, but was mimicked by administration of the NPY Y2-receptor agonist N-acetyl[Leu28,Leu31]NPY(24-36) (Lacroix et al., 1994). This is consistent with a prejunctional NPY Y2-like receptor-mediated inhibition of transmitter release from parasympathetic nerve terminals.
The prejunctional or neuropeptide Y Y
2
receptor classification was based on actions of peptide YY (13-36) but in many systems this molecule, as well as neuropeptide Y-(13-36), does exhibit pressor activity (Rioux et al., 1986; Lundberg, et al., 1988; Potter et al., 1989). This has been interpreted by some to indicate that in some vascular beds there are two types of neuropeptide Y receptor (both neuropeptide Y Y
1
and neuropeptide Y Y
2
) on postjunctional membranes (Schwartz et al., 1989). However the lack of selectivity of these molecules may be due to retention of partial agonist activity on Y
1
receptors, which permits them to evoke a reduced functional response. We have previously described a 13-36 analog of neuropeptide Y, (Leu
17
, Glu
19
, Ala
21
, Ala
22
, Glu
23
, Leu
28
, Leu
31
) neuropeptide Y-(13-36) (ANA neuropeptide Y-(13-36)) which displayed prejunctional activity equivalent to the whole neuropeptide Y molecule in studies in vivo (Potter et al., 1989). However, this analog still retained significant pressor activity, or neuropeptide Y Y
1
receptor-mediated interactions.
We have also previously described analogs of neuropeptide Y which mimic the action of neuropeptide Y in inhibiting cardiac vagal action but have no pressor action. Consistent with these functional responses are binding studies with one analog, N-acetyl [Leu
28
, Leu
3
] neuropeptide Y-(24-36), which showed significant affinity for the neuropeptide Y Y
2
receptor subtype expressed on the human neuroblastoma cell line SMS-KAN, but no affinity for the neuropeptide Y Y
1
receptor type expressed on the human cell line SK-N-MC (Potter et al., 1994). In addition, this analog did not stimulate the human neuropeptide Y Y
1
receptor expressed in fibroblast cells to induce an increase in cytosolic calcium, although the receptor responds to intact neuropeptide Y.
DISCLOSURE OF INVENTION
The present inventors have now developed novel peptides that mimic responses attributed to activation of neuropeptide Y Y2-like receptors. In in vitro assays these agonists show high affinity at neuropeptide Y Y2 receptors and have low affinity for NPY Y1 receptors. In in vivo assays the new agonists exhibit similar or enhanced NPY Y2-receptor-like agonist activity when compared with N-acetyl [Leu
28
, Leu
31
] neuropeptide Y-(24-36) and they show no pressor or Y
1
-receptor activiy at doses eliciting maximal neuropeptide Y Y2-like agonist action.
Accordingly, in the first aspect the present invention consists in a ligand for a neuropeptide Y receptor having the formula:
X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-X15
wherein
X1 is H, R1-CO or one or two naturally occurring amino acids
X2 is Leu, Ile, Val, Nie, Sar, Gly, Ala, Aib, D-Leu, D-Ile, D-Val, D-Ala or D-Nle;
X3 is Arg, Lys, Orn, Ala, Dbu or His;
X4 is His, Lys, Arg, Ala, Gly, Ser, Thr, Asn, Gln or Aib;
X5 is Tyr, Phe, Ala, Gly, Ser, Thr, Asn, Gln or Aib;
X6 is Leu, Ile, Val, Ala, Arg or Nle;
X7 is Asn, Ala or Gln;
X8 is Leu, Ile, Val, Ala, Aib or Nle;
X9 is Leu, Ile, Val, Ala, Aib or Nle;
X10 is Thr, Ala or Ser

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