Synthesis and structural requirements of N-substituted norapomorphines for affinity and activity at dopamine D-1, D-2, and agonist receptor sites in rat brain.
A series of N-substituted analogues of (R)-(-)-norapomorphine were synthesized to study the optimal structural requirements of the N-alkyl side chain to interact with D-1 and D-2 dopaminergic receptors as well as dopamine (DA) agonist binding sites. Evaluations included testing the affinity of these compounds for DA receptor sites in rat striatal tissue and assessing stereotypy as a behavioral index of dopaminergic activity. The electronic, steric, and lipophilic properties of the N-alkyl side chain were found to be related to affinity, D-2 selectivity, and dopaminergic activity. All 11 compounds evaluated had relatively low affinity at D-1 sites. Optimum D-2 and agonist-site affinity as well as agonist activity were exhibited by N-cyclopropylmethyl (7) greater than or equal to N-allyl (8) greater than or equal to N-propyl (4) or N-ethyl (3) substituted compounds. Branching of the N-alkyl side chain as in N-isopropyl (5) and N-isobutyl (6) markedly reduced the D-2 affinity and activity, presumably due to steric effects. The N-trifluoroethyl (10) and N-pentafluoropropyl (11) derivatives had low affinity for all their dopamine receptor sites and no agonistic activity; evidently, the highly electronegative F atoms decrease basicity of the N atom and therefore decrease the ability of the N atom to be cationic at physiological pH, a proposed requirement for high-affinity binding to DA receptors.
Gao
Y G
YG
Section of Medicinal Chemistry, College of Pharmacy and Allied Health Professions, Northeastern University, Boston, Massachusetts 02115.
Ram
V J
VJ
Campbell
A
A
Kula
N S
NS
Baldessarini
R J
RJ
Neumeyer
J L
JL
D000818:Animals; D001058:Apomorphine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D002462:Cell Membrane / Q000378:metabolism; D055598:Chemical Phenomena; D002621:Chemistry; D003342:Corpus Striatum / Q000378:metabolism; D008297:Male; D008968:Molecular Conformation; D015394:Molecular Structure; D051381:Rats; D011919:Rats, Inbred Strains; D011954:Receptors, Dopamine / Q000187:drug effects / Q000378:metabolism*; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D013239:Stereotyped Behavior / Q000187:drug effects
D011954:Receptors, Dopamine; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; C008668:norapomorphine; D001058:Apomorphine