Pyrroloisoquinoline Antidepressants. 2. In-depth Exploration of Structure-Activity Relationships

J Med Chem. 1987 Aug;30(8):1433-54. doi: 10.1021/jm00391a028.

Abstract

A series of pyrrolo[2,1-a]isoquinolines, and related compounds, were examined for antidepressant-like activity, by virtue of their antagonism of tetrabenazine-induced ptosis and sedation, and inhibition of biogenic amine uptake. Thus, we have identified some of the most potent antagonists of TBZ-induced ptosis and some of the most potent inhibitors of the uptake of dopamine, norepinephrine, and serotonin (in rat brain synaptosomes) ever reported. Compounds of particular note, in this regard, are 52b, 29b, 22b, and 48b, respectively. Biological activity was chiefly manifested by the trans isomeric class. Also, through resolution of four compounds, 7b, 24b, 37b, and 48b, biological activity was found to be associated with the (+) enantiomer subgroup (salts measured at 589 nm in MeOH), corresponding to the 6S, 10bR absolute configuration for 7b, 37b, and 48b, and the 6R,10bR configuration for 24b. An X-ray determination on (+)-24b X HBr established its absolute configuration; configurations for the other compounds were verified by enantiospecific synthesis starting with (+)-(R)-2-phenylpyrrolidine. Regarding the pendant phenyl ring, diverse substitution patterns were investigated. Those substitutions that were particularly unfavorable were 3',4',5'-trimethoxy (20b), 2',3',4',5',6'-pentafluoro (34b), 2'-trifluoromethyl (38b), 3',5'-bis(trifluoromethyl) (42b), 4'-n-butyl (44b), 2'-cyano (47b), 4'-methylsulfonyl (50b), and 2'-carboxy (58b). Exceedingly potent compounds, in one way or another, were 10b-12b, 22b, 23b, 25b, 28b, 29b, 33b, 45b, 48b, 51b-53b. The pattern of aromatic substitution had a strong impact on selectivity in the uptake tests (NE vs. DA vs. 5-HT). Activity was significantly diminished by methyl substitution of 7b at the 5 (65, 66), 6 (61b), or 10b (60b) position, by changing the phenyl group of 7b to cyclohexyl (67b), benzyl (68b), or H (72), by moving the phenyl group of 7b to the 5 (69) or 10b (70) position, by expansion of ring B to an azepine (78b), and by modification of ring C to an azetidine (77b), piperidine (75b), or azepine (74b). The interaction of selected analogues with various CNS receptors is reported. Little affinity was shown for the muscarinic cholinergic receptor, suggesting a lack of anticholinergic side effects. Interestingly, 24b and 33b displayed a high affinity for the serotonin-2 receptor, analogous to mianserin and clomipramine. After the body of data was reviewed, derivatives 24b and 48b were chosen for advanced development.

Publication types

  • Comparative Study

MeSH terms

  • Animals
  • Antidepressive Agents
  • Blepharoptosis / chemically induced
  • Blepharoptosis / prevention & control
  • Brain / drug effects
  • Brain / metabolism*
  • Catecholamines / metabolism*
  • Chemical Phenomena
  • Chemistry
  • Dopamine / metabolism
  • Isoquinolines / chemical synthesis
  • Isoquinolines / metabolism
  • Isoquinolines / pharmacology*
  • Male
  • Molecular Conformation
  • Motor Activity / drug effects
  • Norepinephrine / metabolism
  • Pyrroles / chemical synthesis
  • Pyrroles / metabolism
  • Pyrroles / pharmacology*
  • Rats
  • Rats, Inbred Strains
  • Receptors, Adrenergic, alpha / metabolism
  • Receptors, Dopamine / metabolism
  • Receptors, Serotonin / metabolism
  • Serotonin / metabolism
  • Structure-Activity Relationship
  • Synaptosomes / metabolism
  • Tetrabenazine / antagonists & inhibitors*

Substances

  • Antidepressive Agents
  • Catecholamines
  • Isoquinolines
  • Pyrroles
  • Receptors, Adrenergic, alpha
  • Receptors, Dopamine
  • Receptors, Serotonin
  • Serotonin
  • Dopamine
  • Norepinephrine
  • Tetrabenazine