Neuromedin B receptor antagonists which demonstrate selectivity
First Claim
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1. A method of selectively inhibiting inositol phosphate production in cells induced by neuromedin B, said method comprising the step of contacting said cells with an octapeptide of the formula:
- ##STR8## wherein AA1 is the D- or L-isomer of an aromatic α
-amino acid;
AA2 is the D- or L-isomer of Cys;
AA3 is F5 Phe, Phe, or X-Phe in which X is OH;
AA4 is Trp or an aromatic α
-amino acid;
AA5 is Lys or Orn;
AA6 is Leu, Ile, Nle, Val, Nal, or Phe;
AA7 is the D- or L-isomer of Cys;
AA8 is the D- or L-isomer selected from the group consisting of an aromatic α
-amino acid, Thr and Ser;
each R1 and R2, independently, is H, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, phenyl, naphthyl, C7-12 phenylalkyl, C8-12 phenylalkenyl, C8-12 phenylalkynyl, C11-20 naphthylalkyl, C12-20 naphthylalkenyl, C12-20 naphthylalkynyl, COE, or COOE in which E is C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, phenyl, naphthyl, C7-12 phenylalkyl, C8-12 phenylalkenyl, C8-12 phenylalkynyl, C11-20 naphthylalkyl, C12-20 naphthylalkenyl, or C12-20 naphthylalkynyl, provided that when one of R1 or R2 is COE or COOE, the other must be H;
each R3 and R4 , independently, is H, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, phenyl, naphthyl, C7-12 phenylalkyl, C8-12 phenylalkenyl, C8-12 phenylalkynyl, C11-20 naphthylalkyl, C12-20 naphthylalkenyl, or C12-20 naphthylalkynyl; and
Y is OR5 or NR6 R7 in which each R5, R6 and R7, independently, is H, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, phenyl, naphthyl, C7-12 phenylalkyl, C8-12 phenylalkenyl, C8-12 phenylalkynyl, C11-20 naphthylalkyl, C12-20 naphthylalkenyl, or C12-20 naphthylalkynyl;
provided that AA1 and AA2 cannot both be D-isomers; and
further provided that if AA8 is Thr or Ser, AA6 cannot be Val.
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Abstract
A method of selectively inhibiting biochemical activity of cells induced by neuromedin B. The method includes the step of contacting cells which contain neuromedin B receptor with a cyclic octapeptide, D-Nal-Cys-Tyr-D-Trp-Lys-Val-Cys-Nal-NH2, or an analog thereof.
15 Citations
24 Claims
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1. A method of selectively inhibiting inositol phosphate production in cells induced by neuromedin B, said method comprising the step of contacting said cells with an octapeptide of the formula:
- ##STR8## wherein AA1 is the D- or L-isomer of an aromatic α
-amino acid;AA2 is the D- or L-isomer of Cys; AA3 is F5 Phe, Phe, or X-Phe in which X is OH; AA4 is Trp or an aromatic α
-amino acid;AA5 is Lys or Orn; AA6 is Leu, Ile, Nle, Val, Nal, or Phe; AA7 is the D- or L-isomer of Cys; AA8 is the D- or L-isomer selected from the group consisting of an aromatic α
-amino acid, Thr and Ser;each R1 and R2, independently, is H, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, phenyl, naphthyl, C7-12 phenylalkyl, C8-12 phenylalkenyl, C8-12 phenylalkynyl, C11-20 naphthylalkyl, C12-20 naphthylalkenyl, C12-20 naphthylalkynyl, COE, or COOE in which E is C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, phenyl, naphthyl, C7-12 phenylalkyl, C8-12 phenylalkenyl, C8-12 phenylalkynyl, C11-20 naphthylalkyl, C12-20 naphthylalkenyl, or C12-20 naphthylalkynyl, provided that when one of R1 or R2 is COE or COOE, the other must be H; each R3 and R4 , independently, is H, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, phenyl, naphthyl, C7-12 phenylalkyl, C8-12 phenylalkenyl, C8-12 phenylalkynyl, C11-20 naphthylalkyl, C12-20 naphthylalkenyl, or C12-20 naphthylalkynyl; and Y is OR5 or NR6 R7 in which each R5, R6 and R7, independently, is H, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, phenyl, naphthyl, C7-12 phenylalkyl, C8-12 phenylalkenyl, C8-12 phenylalkynyl, C11-20 naphthylalkyl, C12-20 naphthylalkenyl, or C12-20 naphthylalkynyl; provided that AA1 and AA2 cannot both be D-isomers; and
further provided that if AA8 is Thr or Ser, AA6 cannot be Val. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13)
- ##STR8## wherein AA1 is the D- or L-isomer of an aromatic α
-
14. A method of selectively inhibiting inositol phosphate production in cells induced by neuromedin B, said method comprising the step of contacting said cells with an octapeptide of the formula:
- ##STR9## wherein AA1 is the D- or L-isomer of an aromatic α
-amino acid;AA2 is the D- or L-isomer of Cys; AA3 is F5 Phe, Phe, or X-Phe in which X is OH; AA4 is Trp or an aromatic α
-amino acid;AA6 is Thr or Ser; AA7 is the D- or L-isomer of Cys; AA8 is the D- or L-isomer selected from the group consisting of an aromatic α
-amino acid;each R1 and R2, independently, is H, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, phenyl, naphthyl, C7-12 phenylalkyl, C8-12 phenylalkenyl, C8-12 phenylalkynyl, C11-20 naphthylalkyl, C12-20 naphthylalkenyl, C12-20 naphthylalkynyl, COE, or COOE in which E is C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, phenyl, naphthyl, C7-12 phenylalkyl, C8-12 phenylalkenyl, C8-12 phenylalkynyl, C11-20 naphthylalkyl, C12-20 naphthylalkenyl, or C12-20 naphthylalkynyl, provided that when one of R1 or R2 is COE or COOE, the other must be H; each R3 and R4, independently, is H, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, phenyl, naphthyl, C7-12 phenylalkyl, C8-12 phenylalkenyl, C8-12 phenylalkynyl, C11-20 naphthylalkyl, C12-20 naphthylalkenyl, or C12-20 naphthylalkynyl; and Y is OR5 or NR6 R7 in which each R5, R6 and R7, independently, is H, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, phenyl, naphthyl, C7-12 phenylalkyl, C8-12 phenylalkenyl, C8-12 phenylalkynyl, C11-20 naphthylalkyl, C12-20 naphthylalkenyl, or C12-20 naphthylalkynyl;
provided that AA1 and AA2 cannot both be D-isomers. - View Dependent Claims (15, 16, 17, 18, 19, 20, 21, 22, 23, 24)
- ##STR9## wherein AA1 is the D- or L-isomer of an aromatic α
Specification
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Current AssigneeAdministrators Of The Tulane Educational Fund (ADMINISTRATORS|DAVID H. COY), Blomeasure, Inc., Societe de Conseils de Recherches et d'Applications Scientifiques
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Original AssigneeAdministrators Of The Tulane Educational Fund (ADMINISTRATORS|DAVID H. COY), Biomeasure, Inc. (Ipsen Sa)
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InventorsTaylor, John E., Coy, David H.
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Primary Examiner(s)Warden, Jill
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Assistant Examiner(s)DAVENPORT, AVIS MICHELLE
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Application NumberUS08/078,419Time in Patent Office866 DaysField of Search530/311, 530/328, 530/, 514/15, 514/16, 514/17US Class Current514/19.7CPC Class CodesA61K 38/31 SomatostatinsA61P 43/00 Drugs for specific purposes...C07K 14/6555 at least 1 amino acid in D-...
