1208 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 8
Communications to the Editor
551. (b) Forray, C.; Bard, J . A.; Wetzel, J . M.; Chiu, G.; Shapiro,
E.; Tang, R.; Lepor, H.; Hartig, P. R.; Weinschank, R. L.;
Branchek, T. A.; Gluchowski, C. The Alpha-1-Adrenergic Recep-
tor that Mediates Smooth Muscle Contraction in the Human
Prostate has the Pharmacological Properties of the Cloned
Human Alpha-1c Subtype. Mol. Pharmacol. 1994, 45, 703-708.
(c) Chapple, C. R.; Burt, R. P.; Andersson, P. O.; Greengrass,
P.; Wyllie, M.; Marshall, I. Alpha-1-Adrenoceptor Subtypes in
the Human Prostate. Br. J . Urol. 1994, 74, 585-589.
A-61603 pressor responses, it appears that R1b receptors
do not contribute to the phenylephrine pressor response.
By similar reasoning, R1b receptors do not appear to play
a significant role in the maintenance of basal mean
arterial pressure in SHR. However, at present, to
clearly demonstrate in vivo selectivity versus pure R1b-
or R1d-mediated physiological responses is problematic
due to the lack of selective agonists for these subtypes.
Therefore, the lack of in vivo potency versus phenyl-
ephrine- or A-61603-mediated increases in mean arte-
rial pressure, or lack of hypotensive potency in SHR
should be interpreted cautiously. The lack of in vivo
potency may be due to factors other than subtype
selectivity such as plasma protein binding or rapid
metabolism. Nevertheless, if the in vivo potency and
selectivity parallels the in vitro potency and selectivity,
then these data suggest that the R1b receptor subtype
may not be important in mediating phenylephrine-
induced increases in mean arterial pressure in rats, nor
may it be important for the maintenance of basal blood
pressure in anesthetized SHR.
(6) (a) For KMD-3213: Shibata, K.; Foglar, R.; Horie, K.; Obika,
K.; Sakamoto, A.; Ogawa, S.; Tsujimoto, G. KMD-3213, a Novel,
Potent, R1a-Adrenoceptor-Selective Antagonist: Characterization
Using Recombinant Human R1-Adrenoceptors and Native Tis-
sues. Mol. Pharmacol. 1995, 48, 250-258. (b) For Rec 15/2739:
Testa, R.; Guarneri, L.; Taddei, C.; Poggesi, E.; Angelico, P.;
Sartani, A.; Leonardi, A.; Gofrit, O. N.; Meretyk, S.; Caine, M.
Functional Antagonistic Activity of Rec 15/2739, a Novel Alpha-1
Antagonist Selective for the Lower Urinary Tract, on Norad-
renaline-Induced Contraction of Human Prostate and Mesenteric
Artery. J . Pharmcol. Exp. Ther. 1996, 277, 1237-1246. (c) For
RS-17053: Ford, A. P. D. W.; Arredondo, N. F.; Blue, D. R.;
Bonhaus, D. W.; J asper, J .; Kava, M. S.; Lesnick, J .; Pfister, J .
R.; Shieh, I. A.; Vimont, R. L.; Williams, T. J .; McNeal, J . E.;
Stamey, T. A.; Clarke, D. E. RS-17053 (N-[2-(2-Cyclopropyl-
methoxyphenoxy)ethyl]-5-chloro-R,R-dimethyl-1H-indole-3-etha-
namine hydrochloride), a Selective R1a-Adrenoceptor Antagonist,
Displays Low Affinity for Functional R1-Adrenoceptors in Human
Prostate: Implications for Adrenoceptor Classification. Mol.
Pharmacol. 1996, 49, 209-215.
Con clu sion . We have described the synthesis of
some novel, potent, and selective R1b receptor antago-
nists related to prazosin. The effects induced by the
modest structural changes to the 2-N-piperazinyl-4-
aminoquinazoline containing R1 antagonists described
herein suggest a viable strategy for introducing subtype
selectivity in other series of nonselective or less-selective
R1 receptor antagonists.
(7) (a) Myer, M. D.; Altenbach, R. J .; Hancock, A. A.; Buckner, S.
A.; Knepper, S. M.; Kerwin, J . F. Synthesis and in Vitro
Characterization of N-[5-Dihydro-1H-imidazol-2-yl)-2-hydroxy-
5,6,7,8-tetrahydronaphthalen-1-yl]methanesulfonamide and Its
Enantiomers: A Novel Selective R1A Receptor Agonist. J . Med.
Chem. 1996, 39, 4116-4119. (b) Taniguchi, N.; Hamada, K.;
Ogasawara, T.; Ukai, Y.; Yoshikuni, Y.; Kimura, K. NS-49, an
R
1A-Adrenoceptor Agonist, Selectivity Increases Intraurethral
Pressure in Dogs. Eur. J . Pharmacol. 1996, 318, 117-122.
(8) (a) Giardina, D.; Crucianelli, M.; Melchiorre, C.; Taddei, C.;
Testa, R. Receptor Binding Profile of Cyclazosin, a New R1B
-
Ack n ow led gm en t. We thank Craig A. Coburn,
Robert M. DiPardo, and William C. Lumma (Merck &
Co., Inc.) for valuable discussions. The authors also
thank the reviewers for insightful comments.
Adrenoceptor Antagonist. Eur. J . Pharmacol. 1995, 287, 13-
16. (b) Giardina, D.; Crucianelli, M.; Romanelli, R.; Leonardi,
A.; Poggesi, E.; Melchiorre, C. Synthesis and Biological Profile
of the Enantiomers of [4-(4-Amino-6,7-dimethoxyquinazolin-2-
yl)-cis-octahhydroquinoxalin-1-yl]furan-2-ylmethanone (Cycla-
zosin), a Potent Competitive R1B-Adrenoceptor Antagonist. J .
Med. Chem. 1996, 39, 4602-4607.
Refer en ces
(9) Goetz, A. S.; King, H. K.; Ward, S. D. C.; True, T. A.; Rimele, T.
J .; Saussy, D. L. BMY 7378 is a Selective Antagonist of the D
Subtype of R1-Adrenoceptors. Eur. J . Pharmacol. 1995, 272, R5-
R6.
(10) Rossen, K.; Weissman, S. A.; Sager, J .; Reamer, R. A.; Askin,
D.; Volante, R. P.; Reider, P. J . Asymmetric Hydrogenation of
Tetrahydropyrazines: Synthesis of (S) Piperazine-2-tert-butyl-
carboxamide, an Intermediate in the Preparation of HIV Pro-
tease Inhibitor Indinavir. Tetrahedron Lett. 1995, 36, 6419-
6422.
(11) Wada, T.; Otsu, T.; Hasegawa, Y.; Mizuchi, A.; Ono, H. Char-
acterization of R1-Adrenergic Subtypes in the Rat Spinal Cord.
Eur. J . Pharmacol. 1996, 312, 263-266.
(12) Three rats were dosed iv with 9 at 3 mg/kg, and the plasma
was assayed by LCMS for parent compound. The mean Cmax was
1.05 µM and the t1/2 was 0.5 h.
(1) For example, Prazosin: Graham, R. M.; Pettinger, W. A. Drug
Therapy: Prazosin. N. Engl. J . Med. 1979, 300, 232-236.
(2) Caine, M.; Raz, S.; Zeigler, M. Adrenergic and Cholinergic
Receptors in the Human Prostate, Prostatic Capsule and Bladder
Neck. Br. J . Urol. 1975, 47, 193-202.
(3) Caine, M.; Pfau, A.; Perlberg, S. The Use of Alpha-adrenergic
Blockers in Benign Prostatic Obstruction. Br. J . Urol. 1976, 48,
255-263.
(4) (a) Schwinn, D. A.; Lomasney, J . W.; Lorenz, W.; Szklut, P. J .;
Fremeau, R. T.; Tany-Feng, T. L.; Caron, M. G.; Lefkowitz, R.
J .; Cotecchia, S. Molecular Cloning and Expression of the
cDNA for a Novel R1-Adrenergic Receptor Subtype. J . Biol.
Chem. 1990, 265, 8183-8189. (b) Schwinn, D. A.; J ohnston, G.
L.; Page, S. O.; Mosley, M. J .; Wilson, K. H.; Worman, N. P.;
Campbell, S.; Roock, M. O.; Furness, L. M.; Parry-Smith, D. J .;
Peter, B.; Beiley, D. S. Cloning and Pharmacological Charac-
terization of Human Alpha-1 Adrenergic Receptors: Sequence
Corrections and Direct Comparison With Other Species. J .
Pharmacol. Exp. Ther. 1995, 272, 134-142.
(13) Although we have no explanation for this difference, a similar
species effect was observed for rauwolscine between the R2a
adrenergic receptors from human and rodent sources. For a
discussion of this example, please see: Heible, J . P.; Bondinell,
W. E.; Ruffolo, R. R. J . Med. Chem. 1995, 38, 3415-3444.
(5) (a) Price, D. T.; Schwinn, D. A.; Lomasney, J . W.; Allen, L. F.;
Caron, M. G.; Lefkowitz, R. J . Identification, Quantification, and
Localization of mRNA for Three Distinct Alpha-1 Adrenergic
Receptor Subtypes in Human Prostate. J . Urol. 1993, 150, 546-
J M980053F