Synthesis and pharmacological characterization of 2-(4-chloro-3-hydroxyphenyl)ethylamine and N,N-dialkyl derivatives as dopamine receptor ligands.
2-(4-Chloro-3-hydroxyphenyl)ethylamine (4) and some derivatives were synthesized as dopamine (DA) receptor ligands. Amine 4 retains the dopaminergic pharmacophore 2-(3-hydroxyphenyl)-ethylamine, and the chlorine atom replaces the "para" hydroxyl group of DA. The derivatives 18a-e were obtained by introducing on the nitrogen of amine 4 the n-propyl and 2-phenylethyl or 3-phenylpropyl groups which can be accommodated by the D-2 receptor lipophilic sites 3C and pi 3, respectively. The affinity and selectivity of these compounds for D-1 and D-2 subtypes was determined in radioligand competition assays for the DA receptors of rat striatum membranes using [3H]SCH 23390 (D-1 selective) and [3H]spiperone (D-2 selective) as radioligands. The amine 4 shows about 7-fold lower affinity than DA for both sites and is not able to discriminate between the two subtypes of DA receptors. The introduction of two n-propyl groups (18a) on the nitrogen atom reduces by one-half and doubles the affinity for D-1 and D-2 binding sites, respectively. The substitution of an n-propyl group with different alkylphenyl groups, to give compounds 18b-e, increases the affinity for the D-2 subtype from 19-fold to 36-fold. These compounds have the same affinity at the D-2 site as the DA agonist N-n-propyl-N-(2-phenylethyl)-2-(3-hydroxyphenyl)-ethylamine (2a) and are about 20 times more selective than DA for this binding site. In the assay for D-2 receptor mediated inhibition of adenylate cyclase activity, all the tested compounds behaved as D-2 agonists; N-n-propyl-N-[2(4-hydroxyphenyl)ethyl]- (18d) and N-n-propyl-N-(2-phenyl-ethyl)-2-(4-chloro-3-hydroxyphenyl)ethylamine (18b) were more effective than DA or 2a. On the other hand, all compounds were less effective than DA in stimulation of adenylate cyclase activity in rat striatal homogenates, a kind of effect which is mediated by the D-1 subtype of DA receptors. These results suggest that the nitrogen substitution enhances the affinity and selectivity for the D-2 receptor. In the adenylate cyclase assay, the compounds behave as potent D-2 agonists.
Department of Chemical Sciences, University of Camerino, Italy.
F
F
Claudi
G
G
Giorgioni
A
A
Di Stefano
M P
MP
Abbracchio
A M
AM
Paoletti
W
W
Balduini
D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D001667:Binding, Competitive; D001921:Brain / Q000187:drug effects / Q000201:enzymology; D015259:Dopamine Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010627:Phenethylamines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D011954:Receptors, Dopamine / Q000187:drug effects*; D013329:Structure-Activity Relationship; D014439:Tyramine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
D015259:Dopamine Agents; D010627:Phenethylamines; D011954:Receptors, Dopamine; C078275:2-(4-chloro-3-hydroxyphenyl)ethylamine; D000262:Adenylyl Cyclases; D014439:Tyramine