3-Phenyl-1-indanamines. Potential antidepressant activity and potent inhibition of dopamine, norepinephrine, and serotonin uptake.
A series of 3-phenyl-1-indanamines was synthesized and tested for potential antidepressant activity and for inhibition of dopamine (DA), norepinephrine (NE), and serotonin (5-HT) uptake. Trans isomers were generally potent inhibitors of DA, NE, and 5-HT uptake, while cis isomers preferentially inhibited the uptake of 5-HT. The affinity for the DA-uptake site was very dependent on the aromatic substitution pattern where highest potency was found for 3',4'-dichloro substituted compounds (45). This substitution pattern also resulted in high affinity for the NE-and 5-HT-uptake sites, but potent 5-HT-uptake inhibiting activity could also be obtained with other substitution patterns. Only small amines could be accommodated at the 5-HT-uptake site while larger amines such as piperazine could be accommodated both at the DA-and NE-uptake sites. The observed structure-activity relationships were explained from the results of superimpositions of a trans (45) and cis (72) isomer with 5-HT and DA, respectively, in relation to a proposed three-point binding of the uptake inhibitors at the uptake sites. Finally, comparison of the structures of the 3-phenyl-1-indanamines with other newer bicyclic catecholamine- and/or serotonin-uptake inhibitors revealed common structural elements important for potent DA-, NE-, and/or 5-HT-uptake inhibition.
D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D055598:Chemical Phenomena; D002621:Chemistry; D004298:Dopamine / Q000378:metabolism*; D007189:Indans / Q000138:chemical synthesis / Q000494:pharmacology*; D007192:Indenes / Q000494:pharmacology*; D051379:Mice; D009638:Norepinephrine / Q000378:metabolism*; D011817:Rabbits; D011941:Receptors, Adrenergic / Q000187:drug effects / Q000378:metabolism; D011954:Receptors, Dopamine / Q000187:drug effects / Q000378:metabolism; D011985:Receptors, Serotonin / Q000187:drug effects / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D000928:Antidepressive Agents; D007189:Indans; D007192:Indenes; D011941:Receptors, Adrenergic; D011954:Receptors, Dopamine; D011985:Receptors, Serotonin; D012701:Serotonin; D004298:Dopamine; D009638:Norepinephrine