Mapping the Dopamine Receptor: Some Primary and Accessory Binding Sites

The crystal structure of the neuroleptic agent (±)-deoxybutaclamol and its significance for the topography of the central dopamine receptor

“…(F)-deoxybutaclamol, 2, was found to be virtually (k)-Butaclamol has been demonstrated to be a equipotent to (*)-butaclamol using in uiuo (13) and high-affinity dopamine receptor antagonist (10, 1 I), in uitro (15) models of dopamine receptor blockade. and its ability to bind to the dopamine receptor has In contrast, the presence of the tert-butyl or other been ascribed to the presence in its semirigid similar lipophilic group at the 3-position of the benz~~ycloheptapyridoisoquinoline nucleus of an benzocycloheptapyridoisoquinoline nucleus was extended phenylethylamine pharmacophore (12), found to be critical for dopamine receptor anthe nitrogen atom and phenyl ring of which bind to tagonist (13).…”

“…and its ability to bind to the dopamine receptor has In contrast, the presence of the tert-butyl or other been ascribed to the presence in its semirigid similar lipophilic group at the 3-position of the benz~~ycloheptapyridoisoquinoline nucleus of an benzocycloheptapyridoisoquinoline nucleus was extended phenylethylamine pharmacophore (12), found to be critical for dopamine receptor anthe nitrogen atom and phenyl ring of which bind to tagonist (13). primary binding sites on the receptor mat-This necessity for the presence of a lipophilic romolecule (13,14).…”

“…and its ability to bind to the dopamine receptor has In contrast, the presence of the tert-butyl or other been ascribed to the presence in its semirigid similar lipophilic group at the 3-position of the benz~~ycloheptapyridoisoquinoline nucleus of an benzocycloheptapyridoisoquinoline nucleus was extended phenylethylamine pharmacophore (12), found to be critical for dopamine receptor anthe nitrogen atom and phenyl ring of which bind to tagonist (13). primary binding sites on the receptor mat-This necessity for the presence of a lipophilic romolecule (13,14). It was suggested (12) that the group confirmed the existence of a l i~o~h i l i c acceshydroxyl and tert-butyl groups of (+)-butaclamol sory binding site and has led to the proposal (13,14) contribute to the affinity between ligand and re-of a model of the dopamine receptor which inc0rp0-ceptor through binding to accessory binding sites rates primary as well as accessory binding sites.…”

“…primary binding sites on the receptor mat-This necessity for the presence of a lipophilic romolecule (13,14). It was suggested (12) that the group confirmed the existence of a l i~o~h i l i c acceshydroxyl and tert-butyl groups of (+)-butaclamol sory binding site and has led to the proposal (13,14) contribute to the affinity between ligand and re-of a model of the dopamine receptor which inc0rp0-ceptor through binding to accessory binding sites rates primary as well as accessory binding sites. on the receptor macromolecule.…”

Modelling the binding step in dopamine receptor–antagonist interactions

“…In the case of the rigid molecules in the butaclamol series, a slight modification of the positioning of the ring eliminates activity (2). Receptor mapping studies provided the receptors' topography, most importantly the three-dimensional location of the zones corresponding to the two primary sites (3,4). The superposition of the pharmacophores (N atom-chain -aromatic ring) -corresponding to the antagonists with flexible chains and belonging to a different series -was accomplished with only slight modifications of the chain's conformation ( 5 ) .…”