2-Oxopyrrolidines and 6-oxoperhydropyrrolo[1,2-a]pyrazines as templates in the search for nonpeptide cholecystokinin ligands.
In order to find new classes of non-peptide cholecystokinin (CCK) ligands, the conformational restriction of a series of weak 3-oxoindolizidine-based CCK antagonists has been both decreased and increased. This tactic yielded a series of monocyclic 2-oxopyrrolidine derivatives 4 with selectivity for CCK-A or CCK-B receptors and with slightly improved binding affinity at the CCK-A receptor subtype with respect to the model 3-oxoindolizidines. In contrast, the incorporation of the Trp residue at the secondary amino group of a pyrrolo[1,2-a]pyrazine template 5, involving a drastic restriction in the conformational flexibility of the molecule, resulted in a series of bicyclic derivatives that did not bind to CCK receptors at concentrations up to 10(-5) M.
Martín-Martínez
M
M
Instituto de Química Médica (CSIC).
Ballaz
S
S
Latorre
M
M
Herranz
R
R
García-López
M T
MT
Cenarruzabeitia
E
E
Del Río
J
J
González-Muñiz
R
R
D000818:Animals; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D002766:Cholecystokinin / Q000737:chemistry*; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008024:Ligands; D010179:Pancreas / Q000187:drug effects / Q000378:metabolism; D011719:Pyrazines / Q000138:chemical synthesis* / Q000494:pharmacology; D011759:Pyrrolidines / Q000138:chemical synthesis* / Q000494:pharmacology; D011949:Receptors, Cholecystokinin / Q000187:drug effects*
D008024:Ligands; D011719:Pyrazines; D011759:Pyrrolidines; D011949:Receptors, Cholecystokinin; D002766:Cholecystokinin