Synthesis and pharmacology of some 2-aminotetralins. Dopamine receptor agonists

McDermed, John D.; McKenzie, Gerald M.; Phillips, Arthur P.

doi:10.1021/jm00238a008

Cited by 142 publications

(50 citation statements)

References 5 publications

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“…Even greater differences are seen when the present results are compared with data obtained in other dopamine receptor models. A-5,6-DTN derivatives that are not agonists of the dopamine vascular receptor have been reported to cause emesis (9,21), attenuate sympathetic nervous system function (6), and cause behavioral changes in rodents by postulated dopaminergic mechanisms (22). Similarly, a number of compounds postulated to decrease prolactin release by activating dopamine receptors in the pituitary are inactive as dopamine vascular receptor agonists (23).…”

Section: Discussionmentioning

confidence: 99%

Conformational requirements for dopamine-induced vasodilation.

Volkman¹,

Kohli²,

Goldberg³

et al. 1977

Proc. Natl. Acad. Sci. U.S.A.

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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...

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Section: Discussionmentioning

confidence: 99%

Conformational requirements for dopamine-induced vasodilation.

Volkman¹,

Kohli²,

Goldberg³

et al. 1977

Proc. Natl. Acad. Sci. U.S.A.

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“…Active circling behaviour was not observed (Table 4 and 5). Discussion 2-Di-n-propylamino-5, 6-dihydroxytetralin is a potent stimulant of dopamine receptors in many central and peripheral systems (McDermed et al, 1975;Mulder et al, 1980;Goldberg & Kohli, 1981). Its ability to stimulate striatal dopamine receptors leading to orobuccolingual movements, 'dyskinetic biting', which are inhibited by dopamine antagonists provides a useful animal model of abnormal movements (Costall et al, 1980).…”

Section: Resultsmentioning

confidence: 99%

Modification of dyskinesias following the intrastriatal injection of prostaglandins in the rodent

Costall

Holmes

Kelly

et al. 1985

British J Pharmacology

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1 The abilities ofprostaglandin El (PGE1), PGE2, PGD2 and PGF2, to antagonize striatal dopamine function were assessed following bilateral and unilateral injections into the striata of the rat and guinea-pig.2 Three tests were used to assess the effects of the bilateral injections, ability to antagonize dyskinetic biting induced by 2-di-n-propylamino-5, 6-dijiydroxytetralin (0.025 mg kg'-s.c.), ability to antagonize stereotyped behaviour induced by apomorphine (0.5 or 2 mg kg-' s.c.) and ability to induce catalepsy. Asymmetry/circling behaviour revealed on challenge with apomorphine (0.25 mg kg-'s.c.) was measured following unilateral injection into the striatum. 3 In the rat, dyskinetic biting induced by 2-di-n-propylamino-5, 6-dihydroxytetralin was antagonized by PGEI (0.001-1 yg) and PGE2 (0.00001 -1 -g) but not by PGD2 or PGF2, (1 ftg). Stereotyped behaviour induced by apomorphine was not antagonized by any of the prostaglandins. A weak catalepsy was induced by PGEI (1 gg only), PGE2 (0.001 -1 g) and PGD2 (0.001 -1 -tg) but not by PGF2,. Asymmetry and circling behaviour was only observed following the unilateral injection into the striatum of PGE1 and PGD2 (0.01-1 jg) and challenge with apomorphine. 4 In the guinea-pig the actions ofPGE, and E2 were compared with those of PGF2,.. Dyskinetic biting induced by 2-di-n-propylamino-5, 6-dihydroxytetralin was antagonized by bilateral injections into the striatum of PGE2 (0.001-1 fg), but not PGE1 (0.5 jig) and PGF2, (1 pg) but not PGE, (0.5 jig) and PGFu (lJAg). Similar injections of PGE1, E2 and F2, all failed to antagonize apomorphine-induced stereotyped behaviour, or to induce catalepsy. PGE, (0.01-0.5 fig) and PGE2 (0.002-1 pg), but not PGF2e, caused asymmetry following unilateral injection into the striatum and peripheral challenge with apomorphine. 5 It is concluded that the major effect in the striatum of the prostaglandins of the E series is to antagonize dyskinetic biting; this action is not shared by other prostaglandins tested, and does not reflect a generalised ability to antagonize striatal dopamine function. It is suggested that the actions of the prostaglandins to modify differentially dopamine-dependent behaviours from the striatum may reflect activity at a site subsequent to the dopamine receptor.

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“…Many efforts have been made to reduce the conformational flexibility of the arylethylamine moiety; 5,6-dihydroxy-l,2,3,4-tetrahydro-2-naphthalenamine, (II) (Cannon, Kin, Aleem & Long, 1972;McDermed, McKenzie & Phillips, 1975;Shep-OH OH g)…”

Section: Commentmentioning

confidence: 99%

“…Racemic 5,6-ADTN has been synthesized in many laboratories (McDermed et al, 1975;Horn et al, 1978;Sprenger, Cannon, Barman & Burkman, 1969;Mitsuhashi, Adachi, Shimizu, Nomura & Shiotani, 1972;Cannon & Costal, 1977), but none of the synthetic routes seem to be suitable on a multigram scale owing to their overall low yield. To overcome this difficulty, we studied an alternative route which does not require any purification by chromatography and which gives an improved overall yield.…”

Section: Commentmentioning

confidence: 99%