Drug design via pharmacophore identification. Dopaminergic activity of 3H-benz[e]indol-8-amines and their mode of interaction with the dopamine receptor

Abstract

The design and synthesis of a series of 3H-benz[e]indol-8-amines are described. Two of the compounds are potent, orally active dopaminergic agents as established by their ability to induce contralateral turning in rats with unilateral 6-hydroxydopamine-induced lesions of the nigrostriatal pathway, to induce ambulation in rats rendered akinetic by bilateral injections of 6-hydroxydopamine into the anterolateral hypothalamus, and to antagonize reserpine-induced catalepsy in mice. The dopamine agonist activity of the 3H-benz[e]indol-8-amines establishes that a pyrrolo ring and a phenolic hydroxyl group can interact similarly with the dopamine receptor and provides evidence for the existence of a hydrogen-bond acceptor nucleus on the dopamine receptor macromolecule that is involved in the behavioral manifestations of dopamine agonists.

Bioisosterism: A Rational Approach in Drug Design

“…Benz[ e ]indole ( 67 , Figure ), the pyrrolo analogue of the dopaminergic agonist ( 69 ), − displays potent dopaminergic properties, is orally active and has a longer duration of action than 69 . The effectiveness of the pyrrolo ring of 67 as a bioisosteric replacement for the phenolic hydroxyl group has been ascribed to the ability of both groups to hydrogen bond to a common acceptor nucleus on the dopamine receptor . Evidence for the involvement of the hydrogen bond formation being related to the success of this bioisosteric replacement was provided by the lack of activity observed with the N -methylpyrrolo analogue 68 .…”

6,7,8,9-Tetrahydro-N,N-di-n-propyl-3H-benzindol-8-amines. Derivatives as Potent and Orally Active Serotonin 5-HT1A Receptor Agonists

“…6 This gave an indication of the direction of a possible H-bond of 7-OH-DPAT (lb) in the dopamine site of the Da receptor even though the possibility that compound 3 is poorly active by steric interference cannot be outruled. Later Wikstróm et al 7 showed that compound 2b, the dimethyl analog of 2a, possesses considerable 5-HTia agonist properties in addition to its dopaminergic activity, reported by Asselin et al 1 It was speculated that the high electron density in the indole 3-position (corresponding to 1-position of 2b), resembled the 8-oxygen in 8-hydroxy-2-(Ñ,2V-dipropylamino)-l,2,3,4-tetrahydronaphthalene (8-OH-DPAT, la), the well-studied standard serotonin 5-HTia agonist.8-15 If one considers hydrogen bond attraction to the receptor protein, it is possible that in the case of 2b the partial negative charge of the -electron cloud nearby Cl serves as a hydrogen bond acceptor, since the hydrogen at Cl presumably is poor as a donor. 16 However, the relatively low binding (compared to 8-OH-DPAT) of the dimethyl compound 2b indicated that a better probe for this hypothesis would be compound 2a.…”

“…This approach has been useful for determining the nature of the hydrogen bonding between phenol-containing ligands and receptor proteins. [1][2][3][4] For example Asselin et al1 demonstrated that the "indolic" aminotetralin 2a (Figure 1) showed dopaminergic effects and thus mimicked the action of 7-hydroxy-2-(iV^V-dipropylamino)-l,2,3,4-tetrahydronaphthalene (7-OH-DPAT, lb). It was pointed out that, since the lone pairs in the indole nitrogen of 2a cannot participate in a H-bond (due to its contribution to the aromaticity), the indole NH moiety can only participate as a H-bond donor (electron-pair acceptor).…”

Synthesis of Pyridazine and Pyrrole Analogues of 2‐Aminotetralin as Potential Dopaminergics

“…Compounds 3–5 are examples of heterocyclic isosteres of hydroxy‐2‐aminotetralins, which were shown to possess DA agonist activity (Fig. ) . This encouraged us to replace the phenolic portion of 2‐aminotetralin with ester and pyridine‐substituted pyridazines and pyrroles may be the compounds with potential dopaminergic activities.…”