Conformational requirements for dopamine-induced vasodilation.

Abstract

ABSIRACT The availability of a series of semi-rigid analogs of dopamine and epinine has made it possible to investigate the conformational requirements for action on dopamine and 2-adrenergic vascular receptors. The analogs were screened for dopamine-agonist action by intra-arterial injections into the renal vascular bed and for P2-adrenergic activity by similar injections into the femoral vascular bed in dogs pretreated with phenoxybenzamine. 2-Amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene and its N-methyl derivative (analogous to the trans P rotamer of dopamine) exhibited pronounced dopamine-agonist activity and minimal 02-adrenergic activity. In contrast, the semi-rigid analog of the trans a rotamer of dopamine (2-amino-5,6-dihydroxy-1,2,3,4-tetrahydronaphthalene; A-5,6-DTN) and its N-methyl derivative exerted pronounced #2-adrenergic activity but were inactive as dopamine agonists.6,7-Dihydroxytetrahydroisoquinoline,a semirigid analog of the cis P rotamer of dopamine, did not produce renal vasodilation. These results indicate that a conformation of dopamine similar to that found in A-6,7-DTN is required for dopamine-vascular activity, while the conformation found in A-5,6-DTN is preferred for interaction with #2-adrenergic receptors. Dopamine can cause vasodilation by several mechanisms (1).Vasodilation can be induced directly by action on 32radrenergic or dopamine vascular receptors (2) and indirectly by action on receptors in autonomic ganglia (3, 4) and postganglionic sympathetic nerves (5, 6). Because the dopamine molecule is flexible and can assume a variety of conformations, it has not been possible to determine whether a specific conformation is required for each of these diverse actions. A possible approach to this problem has been provided recently by the demonstration that a semi-rigid analog of dopamine, 2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene (A-6,7-DTN), met all the criteria of a dopamine agonist in the canine renal and mesenteric vascular beds (7). Because the side chain of the dopamine moiety contained within A-6,7-DTN is fixed in a fully extended position with the amino group trans to the phenyl ring, these results suggested that this conformation of dopamine (trans ,B rotamer) may be required for activation of dopamine receptors. However, dopamine can exist in yet another trans conformation (trans a rotamer) as in 2-amino-5,6-dihydroxy-1,2,3,4-tetrahydronaphthalene , in which the phenyl ring has undergone a 1800 rotation about the phenyl-C-1 bond (see Fig. 1). Previous studies with certain derivatives of A-5,6-DTN indicated that they exert dopamine-like activity in the central nervous system, because they are potent emetic agents and produce gnawing behavior in mice (8, 9). Some of these analogs have also been shown to produce typical (32-adrenergic actions (10).Accordingly, we have compared the relative ,32-adrenergicThe costs of publication of this article were defrayed in part by the payment of page charges from funds made available to support the research which is the su...

Comparison of the Binding of [3H]Spiperone and [3H]Domperidone in Homogenates of Mammalian Retina and Caudate Nucleus

“…In contrast, 5,6-dihydroxy-2-aminotetralin (5,6-diOH ATN), which holds the dopamine skeleton in its a-rotameric cis extreme was some 120 times less active. A similar preference for the 6,7-dihydroxy analogue has been observed previously in several dopaminergic systems (Volkman et al, 1977;Woodruff et al, 1977). Furthermore, N , N-n-dipropyl-5,6-dihydroxy aminotetralin (N, N-n-dipropyl-5,6-diOH ATN), a potent dopaminergic agonist (Cannon et al, 1978) with an IC,, value of 30 nM, was the most potent agonist tested at displacing stereospecific C3H]spiperone binding in the bovine retina ( Fig.…”

.alpha.- and .beta.-Adrenoceptors: From the Gene to the Clinic. 2. Structure-Activity Relationships and Therapeutic Applications

“…Structural analogs of clonidine, such as St-91 (113) and SK&F 35886 (114), although potent a2-adrenoceptor agonists in vitro, do not produce clonidine-like stimulation of central tt2-adrenoceptor in the intact animal. AGN 190851 ( 115) is an analog of UK 14,304 in which the (114) SK&F 35886 (R = CH3) (115) AGN 190851 heterocyclic ring is saturated.65,66 This modification dramatically changes the partition coefficient between octanol and neutral phosphate buffer,66 presumably as a consequence of increasing the basicity of the molecule. AGN 190851 is a potent a2-adrenoceptor agonist in several in vitro assays, such as inhibition of adrenergic neurotransmission in the guinea pig atrium or contraction of canine saphenous vein.…”

The molecular structure of adrenergic and dopaminergic substances

“…There is also one interesting fact concerning the different modes of action of 5,6-dihydroxy-2-aminotetralin and 6,7-dihydroxy-2-aminotetralin that could imply two types of dopamine receptors. Volkman et al (1977) demonstrated that the 6,7-dihydroxylated compound is more potent than the 5,6-dihydroxylated in inducing renal vasodilation in dogs (a D-i receptor effect, according to Kebabian & Calne). Inversely, Costall et al (1977) found the 5,6dihydroxy derivative to be considerably more potent in inducing stereotyped behaviour after direct injection into the nucleus accumbens of rat brain, assumedly a D-2 receptor effect.…”