Conversion of ä-opioid receptor antagonists containing the 2¢,6¢-dimethyl-L-tyrosine (Dmt)- 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (Tic) pharmacophore into potent ä-agonists required a third heteroaromatic nucleus, such as 1H-benzimidazole-2-yl (Bid) and a linker of specified length both located C-terminally to Tic in the general formula H-Dmt-Tic-NHCH( R)-R¢. The distance between Tic and Bid is a determining factor responsible for the acquisition of ä agonism (2, 2¢, 3, 4, 6) or ä antagonism (8). Compounds containing a C-terminal Ala (1, 1¢), Asp (5), or Asn (7) with an amide (1, 1¢, 5) or free acid group (7) served as ä-antagonist controls lacking the third heteroaromatic ring. A change in chirality of the spacer (2, 2¢) or inclusion of a negative charge via derivatives of Asp (4, 6) resulted in potent ä agonism and moderate í agonism, although ä-receptor affinity decreased about 10-fold for 4 while í affinity fell by over 2 orders of magnitude. Repositioning of the negative charge in the linker altered activity: H-Dmt-Tic-NH-CH(CH2-Bid)COOH (6) maintained high ä affinity (Ki ) 0.042 nM) and ä agonism (IC50 ) 0.015 nM), but attachment of the free acid group to Bid [H-Dmt- Tic-NH-CH2-Bid(CH2-COOH) (9)] reconstituted ä antagonism (Ke ) 0.27 nM). The data demonstrate that a linker separating the Dmt-Tic pharmacophore and Bid, regardless of the presence of a negative charge, is important in the acquisition of opioids exhibiting potent ä agonism and weak í agonism from a parent ä antagonist.
Potent delta-opioid receptor agonists containing the Dmt-Tic pharmacophore
BALBONI, Gianfranco;SALVADORI, Severo;GUERRINI, Remo;
2002
Abstract
Conversion of ä-opioid receptor antagonists containing the 2¢,6¢-dimethyl-L-tyrosine (Dmt)- 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (Tic) pharmacophore into potent ä-agonists required a third heteroaromatic nucleus, such as 1H-benzimidazole-2-yl (Bid) and a linker of specified length both located C-terminally to Tic in the general formula H-Dmt-Tic-NHCH( R)-R¢. The distance between Tic and Bid is a determining factor responsible for the acquisition of ä agonism (2, 2¢, 3, 4, 6) or ä antagonism (8). Compounds containing a C-terminal Ala (1, 1¢), Asp (5), or Asn (7) with an amide (1, 1¢, 5) or free acid group (7) served as ä-antagonist controls lacking the third heteroaromatic ring. A change in chirality of the spacer (2, 2¢) or inclusion of a negative charge via derivatives of Asp (4, 6) resulted in potent ä agonism and moderate í agonism, although ä-receptor affinity decreased about 10-fold for 4 while í affinity fell by over 2 orders of magnitude. Repositioning of the negative charge in the linker altered activity: H-Dmt-Tic-NH-CH(CH2-Bid)COOH (6) maintained high ä affinity (Ki ) 0.042 nM) and ä agonism (IC50 ) 0.015 nM), but attachment of the free acid group to Bid [H-Dmt- Tic-NH-CH2-Bid(CH2-COOH) (9)] reconstituted ä antagonism (Ke ) 0.27 nM). The data demonstrate that a linker separating the Dmt-Tic pharmacophore and Bid, regardless of the presence of a negative charge, is important in the acquisition of opioids exhibiting potent ä agonism and weak í agonism from a parent ä antagonist.I documenti in SFERA sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
