Di-n-propyl groups

The effects of N-substituents on dopamine congeners are numerous and well documented. Generally, compounds active at DA2 receptors retain or have enhanced activity as tertiary amines. By contrast, compounds active at DA receptors generally are most active as primary, or sometimes secondary amines with one major exception substitution of the nitrogen with di-n-propyl groups leads to compounds active at DA receptors. This effect is so powerful that even in dopamine congeners which possess the so-called alpha rotameric moiety, not normally seen in DAi agonists, potent action is observed (28). 

The second, and major, problem with this hypothesis is the fact that N-substitution with propyl groups can ruin concepts of orderly structure-activity relationships. The most glaring example of this is the activity of N,N-di-(n-propyl)-5,6-ADTN in the DA receptor of the renal artery (28). In this case the electron pair must be oriented normal to the plane of the molecule and should not, by the above reasoning, be active. Empirical calculations reveal that the propyl groups essentially "iock the nitrogen so that it cannot rotate about the C(2)-N bond. Thus, the presence of di-n-propyl groups constitutes a unique feature which must somehow distort the receptor so that... 

Replacement of the N,N-di-n-propyl groups of 8-OH-DPAT or 8-MeO-DPAT by smaller or larger di-n-alkyl substituents results in a significant drop in affinity [10]. The rankorder of potency is di-n-propyl > di-n-ethyl > di-n-butyl > di-n-methyl (Table 1). For the smaller di-n-alkyl substituted analogues (Cj-Cg), the (R)-enantiomers are more potent than the (S)-enantiomers. This stereo selectivity however, is reversed if larger di-n-alkyl substituents are introduced. The (S)-enantiomer of the di-n-butyl compound is about two times more potent than the (R)-enantiomer (Table 1). 

Fixation of the N,N-di-n-propyl groups of 8-MeO-DPAT into a piperidine ring decreases affinity by a factor of 29 [11]. 

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See also in sourсe #XX -- [ ]

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