Monophenolic 2-(dipropylamino)indans and related compounds: central dopamine-receptor stimulating activity

Abstract

Monophenolic (2-(dipropylamino)indans and related compounds have been synthesized and tested for central dopamine-receptor stimulating activity, using biochemical and behavioral tests in rats and emesis tests in dogs. The active compounds possess similar relative potencies in eliciting the three different dopamine-receptor mediated effects measured. 4-Hydroxy-2-(dipropylamino)indan was the most potent of the new compounds. The corresponding 5-hydroxy analogue was less active. 4-Hydroxy-2-[(dipropylamino)methyl]indan is a new type of dopaminergic agent with a phenylpropylamine moiety in its framework instead of the phenylethylamine structure, common to most dopamine-receptor agonists. This compound was 10-20 times less active than apomorphine. 6,7,8,9-Tetrahydro-1-hydroxy-N,N-dipropyl-5H-6-benzocycloheptenylamine and 5-hydroxy-2-[(dipropylamino)methyl]tetralin were both inactive. Since the intramolecular distances between functional groups in the indans studied here are different from those in, for example, apomorphine, it is concluded that a certain variation of these distances can be accepted by the receptor. It could also be demonstrated that the position of the OH group on the aromatic ring is of importance for the activity and that emetic activity may be associated with dopaminergic agonists of the indan as well as of the tetralin type of structure.

Derivatives as 5HT1A Receptor Ligands-Past and Present

“…Modification of the non-aromatic ring of the 2-aminotetralins, such as ring contraction (indamines) [44], or ring expansion (benzocycloheptamines) [45] decreases 5-HT 1A affinity (Fig. 2).…”

(+)-UH 232 and (+)-UH 242: Novel stereoselective dopamine receptor antagonists with preferential action on autoreceptors

“…The ability of at least low doses to reduce DOPA formation in reserpinized (18 hours) rats primarily reflects a DA autoreceptor action since no reversal of the reserpine-induced hypomotility was evident in this dose range (0.4-0.8/~mol/kg). (-)-UH 242 (ED 50:0.40 and 0.50~mol/kg for iimbic region and striatum, respectively) was approximately ten times less potent than apomorphine (ED 50:41 and 44 nmol/kg for limbic region and striatum, respectively, from Hacksell et aL, 1981 b) in this model.…”

Receptor regulatory properties evident in the molecular similarity of dopamine receptor ligands and purine nucleotides

“…Fenoldopam, for example, is a highly eOE ective dopamine agonist, despite not being able to attain the extended dopamine conformation. The N± O distance in the dopamine agonist 4-hydroxy-2-(dipropylamino) indan has been calculated at 5.5 A I (Hacksell et al 1981). Maximum bond lengths (A I ) in other agonists used in this study that could correspond to the above dopamine N± O a distance are PTHB 7.5, NO-500 7.4, [2-(1H-indol-4-yl)-ethyl]-dipropylamine 7.4, LY-141865 6.1.…”