The 2-aminotetralin system as a structural base for new dopamine- and melatonin-receptor agents Copinga, Swier

Transcription

1 University of Groningen The 2-aminotetralin system as a structural base for new dopamine- and melatonin-receptor agents Copinga, Swier IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite from it. Please check the document version below. Document Version Publisher's PDF, also known as Version of record Publication date: 1994 Link to publication in University of Groningen/UMCG research database Citation for published version (APA): Copinga, S. (1994). The 2-aminotetralin system as a structural base for new dopamine- and melatoninreceptor agents s.n. Copyright Other than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons). Take-down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim. Downloaded from the University of Groningen/UMCG research database (Pure): For technical reasons the number of authors shown on this cover page is limited to 10 maximum. Download date:

2 GENERAL DISCUSSION An established strategy in medicinal chemistry to develop agonists andfor antagonists of biologically active substances, such as neurotransmitters and hormones, which exert their effects through the interaction with specific receptors, is the rigid analogue approach. This approach involves the creation of conformationally restricted analogues of flexible biologically active substances [I]. Due to their conformational restraint, conformationally restricted analogues may show selectivity for a certain receptor subtype of the biologically active substance they are mimicking. These conformationally restricted analogues can be used as pharmacological tools to gain more information about the mode of action of these biologically active substances. Moreover, they can ultimately lead to clinically applicable drugs. THE SEMI-RIGID 2-AMINOTETRALIN SYSTEM: A STRUCTURAL BASE FOR ANALOGUES OF BIOLOGICALLY ACT~VE SUBSTANCES Considering the molecular structure of the important CNS neurotransmitter dopamine (I), it can be seen that this structure contains a flexible ethylamine side chain. A well-known method to rigidify this structure is the incorporation into a semi-rigid 2- aminotetralin system. This system has been suggested to be the dopaminergic pharmacophore in the classical dopamine-receptor agonist (6aR)-(-)-apomorphine [2]. The 2-aminotetralin system fixes the flexible side chain in an extended trans conformation with the amino group close to the plane through the aromatic ring. Two such dopamine analogues, representing the two possible conformational extremes of the trans coplanar form of dopamine, i. e. 5,6-dihydroxy-2-aminotetralin [5,6-(OH)2-AT, 21 and 6,7-dihydroxy-2-aminotetralin [6,7-(OH)2-AT, 31, exert moderate activity at central dopamine receptors (for reviews, see ref. 3-6). Chart GD.l Rigidification of rotameric conformers of dopamine (1) through incorporation into a semirigid 2-aminotetralin system.

3 Previous SAR studies with analogues of these two 2-aminotetralins revealed that minor changes can lead to Zaminotetralins displaying a certain dopamine-receptor subtype selectivity. In relation to the classical biochemicavpharmacological classification of dopamine receptors in two subtypes, i.e. Dl receptors and D2 receptors [7], it was shown that 5,6-dihydroxy-2-(N,N-di-n-propy1amino)teal [5,6-(OH)2-DPAT, 41 and 6,7-di-hydroxy-2-(N,N-di-n-propy1arnino)teal [6,7-(OH)2-DPAT, 51 act as mixed Dl/D2-receptor agonists, whereas 5-hydroxy-2-(N,N-di-n-propy1amino)tetraIin (5-OH-DPAT, 6) and 7-hydroxy-2-(N,N-di-n-propy1amino)tetralin (7-OH-DPAT, 7) display selectivity for D2-receptors in comparison to their catechol analogues [6, Chart GD.2 Chemical structures of the 2-aminotetralins 4-7. Moreover, N-0434 (8) and N-0437 (9), 5-hydroxy-2-aminotetralins with a N-arylethyl substituent, appeared to be extremely potent and selective D2-receptor agonists [ In contrast, 8-chloro-6,7-dihydroxy-2-aminotetralin (10) and 8-fluoro-6,7- dihydroxy-2-aminotetralin (11) were found to be relatively selective Dl-receptor agonists [14]. Chart GD.3 Chemical structures of the 2-aminotetralins

4 Keeping the pharmacological profiles of the above-mentioned 2-aminotetralins in mind, it is not surprising that 5,6-dihydroxy-2-[N-n-propyl-N-2-(2-thienyl)ethylamino]- tetralin [5,6-(OH)2-PTAT, 121 turns out to be a potent mixed Dl/D2-receptor agonist [15]. The fact that this compound, like all other 2-aminotetralins, contains an asymmetric C-2 atom should not be overlooked. It is not only very common that a certain pharmacological activity of a 2-aminotetralin mainly resides in one enantiomer, but it is also possible that the enantiomers have different pharmacological profiles, e.g. opposite effects. For example, the dopamine-receptor agonist activities of 5,6-(OH)2- DPAT (4) and 5-OH-DPAT (6) mainly reside in the (25)-(-)-enantiomers, whereas the (2R)-(+)-enantiomers are the eutomers of 6,7-(OH)2-DPAT (5) and 7-OH-DPAT (7) [3-61. In the case of N-0437 (9), the (2S)-(-)-enantiomer is the more active one [16,17]. Interestingly, the (2R)-(+)-enantiomer of N-0437 (9) behaves pharmacologically as a partial agonist at the D2 receptor [18]. Thus, this enantiomer can antagonize some dopamine-receptor agonist effects of the (25)-(-)-enantiomer. In analogy, the more active enantiomer of 5,6-(OH)2-PTAT (12) has most likely the 2s absolute configuration. However, this suggestion can only be confirmed by the resolution of 5,6- (OH)2-PTAT (12) in its enantiomers and the subsequent pharmacological evaluation of the individual enantiomers. Chart GD.4 Chemical structure of 5,6-(OH)2-PTAT (12). Previous SAR studies disclosed also that the semi-rigid Zaminotetralin system is not only a structural template for conformationally restricted analogues of dopamine, but also for conformationally restricted analogues of the other catecholamines noradrenaline (13) and adrenaline (14). Particularly, 5,8-dimethoxy-2-aminotetralin (15) was shown to be a selective al-receptor agonist, possesing greater potency than the prototypical al-receptor agonist methoxarnine (16) [19]. Likewise, 1,5,6-trihydroxy-2- (N-i-propy1amino)tetralin (17), a semi-rigid analogue of the mixed Pl/P2-receptor agonist isoprenaline (18) through the addition of an ethylene bridge, appeared to be a potent mixed f3 l/p2-receptor agonist [20]. Chart GD.5 Chemical structures of the catecholamines noradrenaline (13) and adrenaline (14)

5 Chart GD.6 Chemical strutures of the adrenergic agents More surprisingly, it was found that 8-hydroxy-2-(N,N-di-n-propy1amino)tetral (8-OH-DPAT, 20) acts as an agonist of the indolamine serotonin (5-hydroxytqptamine, 19) [21]. The 2-aminotetralin 8-OH-DPAT (20) can be taken as a molecular structure formed from serotonin by rigidification through the addition of a methylene bridge, followed firstly by molecular dissection of the pyrrole part of the indole nucleus, and secondly, by structural modification via N,N-di-n-propylation. Molecular dissection and structural modification are other strategies to develop biologically active agents. In particular, 8-OH-DPAT (20) is a potent, selective 5-HTl~-receptor agonist [22]. This finding indicates that it is not always necessary to incorporate all the functional groups of a biologically active substance in a conformationally restricted analogue to mimic some of its activities. Chart GD.7 Molecular structures of serotonin (19) and the selective 5-HT1~-receptor agonist 8-OH- DPAT (20). In accordance with this line of reasoning, the 2-aminotetralin derivative 8-methoxy- 2-(acetamid0)tetralin (8-MeO-AAT, 22) was developed as a conformationally restricted analogue of melatonin (N-acetyl-5-methoxybyptamine, 21). 8-MeO-AAT (22) appeared to be a melatonin-receptor agonist of moderate potency [ Subsequently, 8-Me0- AAT (22) was used as a lead compound for a series of 8-methoxy-2-amidotetralins with melatonin-receptor agonist properties. It was also shown that the (-)-enhomer of 8- MeO-AAT (22), possessing most likely the 2S absolute configuration, is more active at

6 II &z- 0 N / 0 H ' CH3 Chart GD.8 Chemical stuctures of melatonin (21) and the melatonin-receptop agonist 8-MeO-AAT (22). the retinal melatonin receptor than its (+)-enantiomer. A very common approach to develop antagonists of a biologically active substance is the appendage of a bulky lipophilic group to an agonist or partial agonist of that specific, biologically active substance. This approach led to the development of 4-aryl-2-amidotetralins as potential melatonin-receptor antagonists [23,27]. These compounds possess two asymmetric ring carbon atoms. Hence, cisltrans isomerism as well as optical isomerism is involved. Racemic cis-4-phenyl-2-(acetamido)tetralin (23) is a conformationally restricted melatonin-receptor antagonist of reasonable affinty [23,24,26,27]. This nonindolic melatonin-receptor antagonist, based on the semi-rigid 2-aminotetralin system, is 10 times more potent than the indolic melatonin-receptor antagonist luzindole (N-acetyl-2- benzyltryptamine, 24). Chart GD.9 Chemical structures of cis-4-phenyl-2-(acetamid0)tetralin (23) and luzindole (24). In conclusion, the semi-rigid 2-arninotetralin system can serve as a structural base for the development of conformationally restricted analogues of various biologically active substances, including the catecholamine dopamine (1) and the indolamide melatonin (21). (1) Krogsgaard-Larsen P, Bundgaard H (1991) A Textbook of Drug Design and Development. Harwood Academic Publishers, Chur. (2) Pinder RM, Buxton DA, Green DM (1971) On the dopamine-like action of apomorphine. J Pharm Pharmacol23, (3) Cannon JG (1985) Dopamine agonists: structure-activity relationships. Prog Drug Res 29, (4) Kaiser C, Jain T (1985) Dopamine receptors: functions, subtypes and emerging concepts. Med Res Rev 5,

7 (5) Horn AS (1990) Dopamine receptors. In Hansch C, Sammes PC, Taylor JB, Emmett JC (Eds) Comprehensive Medicinal Chemistry Vol3: Membranes and Receptors. Pergamon Press, Oxford, pp (6) Seiler MP, Bolsterli JJ, Floersheim P, Hagenbach A, Markstein R, Pfmi P, Widmer A, Wiitrich H (1993) Recognition at doparnine receptor subtypes. In Testa B, Kyburz E, Fuhrer W, Giger R (Eds) Perspectives in Medicinal Chemistry. Verlag Helvetica Chimica Acta, Basel, pp (7) Kebabian JW, Calne DB (1979) Multiple receptors for dopamine. Nature 277, (8) Seiler MP, Markstein R (1982) Further characterization of structural requirements for agonists at the striatal dopamine Dl receptor. Studies with a series of monohydroxyaminotetralins on dopamine-sensitive cyclase and a comparison with dopamine receptor binding. Mof Pharmacol22, (9) Seiler MP, Markstein R (1984) Further characterization of structural requirements for agonists at the striatal dopamine D2 receptor and a comparison with those at the striatal dopamine Dl receptor. Stu&es with a series of monohydroxyaminotetralins on acetylcholine release from rat striatum. Mol Pharmacol26, (10) Beaulieu M, Itoh Y, Tepper PC, Horn AS, Kebabian JW (1984) N,N-Disubstituted 2-aminotetralins are potent D2 dopamine receptor agonists. Eur JPharmacol105, (11) Horn AS, Tepper PG, Kebabian JW, PM Beart (1984) N-0434, a very potent and specific new D2 dopamine receptor agonist. Eur J Pharmacol99, (12) Horn AS, Tepper PC, Van der Weide J, Watanabe M, Grigoriadis D, Seeman P (1985) Synthesis and radioreceptor binding activity of N-0437, a new, extremely potent and selective D2 dopamine receptor agonist. Pham Weekbl Sci Ed 7, (13) Van der Weide J, De Vries JB, Tepper PG, Horn AS (1986) Pharmacological profiles of three new, potent and selective dopamine receptor agonists: N-0434, N-0437 and N Eur J Pharmacol125, (14) Weinstock J, Gaitanopoulos DE, Oh HJ, PfeiEer FR, Karash CB, Venslavsky JW, Sarau HM, Flaim KE, Hieble JP, Kaiser C (1986) Synthesis and dopaminergic activity of some halogenated mono- and dihydroxylated 2-aminotetralins. J Med Chem 29, (15) Copinga S, Dijkstra D, De Vries JB, Grol CJ, Horn AS (1993) Synthesis and pharmacological evaluation of 5,6,7,8-tetrahydro-6-[propyl[2-(2-thienyl)eyl]amino]-l,2-~phthaleno1: a novel non-selective dopaminereceptor agonist. Recl Trav Chim Pays-Bas 112, (16) Timmennan W, Westerink BHC, De Vries JB, Tepper PC, Horn AS (1989) Mcrodialysis and striatal doparnine: stereoselective actions of the enantiomers of N Eur J Pharmacol162, (17) Timmennan W, Dubocovich MI,, Westerink BHC, De Vries JE3, Tepper PG, Horn AS (1989) The enantiomers of the dopamine agonist N-0437: in vivo and in vitro effects on the release of striatal dopamine. Eur J Pharmacol166, (18) Timmerman W, Tepper PG, Bohus BGJ, Horn AS (1989) The potential antipsychotic activity of the partial dopamine receptor agonist (+)-N Eur JPharmacol181, (19) DeMarinis RM, Shah DH, Hall RF, Hieble JP, Pendleton RG (1982) a-adrenergic agents. 2. Synthesis and al-agonist activity of 2-aminotetralins. J Med Chem 25, (20) Nishkawa M, Kanno M, Kuriki H, Sugihara H, Motohashi M, Itoh K, Miyashita 0, Oka Y, Sanno Y (1975) Selective P-adrenoceptor activities of tetrahydronaphthalene derivatives. Lije Sci 16, (21) ANidsson LE, Hacksell U, Nilsson JLG, Hjorth S, Carlsson A, Lindberg P, Sanchez D, Wikstr6m H (1981) 8-Hydroxy-2-(di-n-propylamino)tetralin, a new centrally acting 5-hydroxytryptamine receptor agonist. J Med Chem 24, (22) hidsson LE (1985) 8-OH-DPAT Hydrobromide. Drugs Future 10, (23) Horn AS, Dubocovich ML ( ) Preparation of Zamidotetralins as melatonin agonists and antagonists. Eur Pat Appl EP (03 Apr 1991). US Appl (25 Sep 1989). (24) Dubocovich ML, Copinga S, Drijfhout WJ, Horn AS (1992) 2-Amidotetralins: the first nonindolic series of melatonin receptor agonists and antagonists. FASEB J 6, A1559 (Abstr). (25) Copinga S, Tepper PG, Grol CJ, Horn AS, Dubocovich ML (1993) 2-Amido-8-methoxytetralins: a series of nonindolic melatonin-like agents. J Med Chem 36, (26) Dubocovich ML (1993) Melatonin receptor agonists and antagonists. In: Claassen V (Ed) Pharmacochemistry Libray Vol20: Trends in Drug Research. Elsevier Science Publishers, Amsterdam, pp (27) Copinga S, Van Brummelen G, Drijfhout WJ, Tepper PG, Grol CJ, Dubocovich ML (1994) 4-Aryl-2- amidotetralins: nonindolic melatonin-receptor agents. Submittedfor Publication.