Table 1.

Chemical structures and antinociceptive activity of congeners of improgan and ranitidine. Fourteen new furan derivatives (in shaded cells) were synthesized and tested presently. Two compounds (in bold) showed very high antinociceptive potency. Compounds are arranged in order of decreasing potency. Derivatives at the bottom of the table (below the solid line) were either inactive or had low potency.

Ar-Y-P-Z
Compound	Ar	Y	P	Z	ED50a
VUF 5498	2-DMAF	-(CH2)6-	NH-C(=CH-NO2)-NH-	methyl	25 (15-36)
VUF 8294	2-DMAF	-CH2-S-(CH2)2-	NH-C(=N-CN)-NH-	methyl	67 (18-117)b
VUF 5407	4(5)-IM	-(CH2)4-	NH-C(=O)-NH-	phenyl	71 (49-93)c
VUF 4687	4(5)-IM	-(CH2)4-	NH-C(=S)-NH-	phenylethyl	80 ± 9d
VUF 4685	4(5)-IM	-(CH2)4-	NH-C(=S)-NH-	phenyl	81 ± 7d
VUF 5420	4(5)-IM	-(CH2)4-	NH-C(=N-CN)-NH-	methyl	82 (74-90)e
VUF 6914	4(5)-IM	-(CH2)8-	NH-C(=N-CN)-NH-	methyl	82 (70-94)e
VUF 4740	4(5)-IM	-(CH2)6-	NH-C(=S)-NH-	methyl	87 ± 15d
VUF 4582	4(5)-IM	-(CH2)2-	NH-C(=S)-NH-	phenyl	89 (64-114)c
VUF 5405	4(5)-IM	-(CH2)4-	NH-C(=CH-NO2)-NH-	methyl	104 (78-130)c
VUF 4686	4(5)-IM	-(CH2)4-	NH-C(=S)-NH-	benzyl	105 (est)d
VUF 5651	4-Me-5-IM	-(CH2)4-	NH-C(=N-CN)-NH-	methyl	105 (92-119)e
VUF 6913	4(5)-IM	-(CH2)5-	NH-C(=N-CN)-NH-	methyl	106 (90-121)e
CC10	4(5)-IM	Trans-cyclopropyl	NH-C(=N-CN)-NH-	methyl	106 (87-125)e
Ranitidine	2-DMAF	-CH2-S-(CH2)2-	NH-C(=CH-NO2)-NH-	methyl	109 ± 16d
VUF 5497	2-DMAF	-(CH2)4-	NH-C(=CH-NO2)-NH-	methyl	111 (54-168)
VUF 4577	4(5)-IM	-(CH2)2-	NH-C(=S)-NH-	methyl	117 (90-144)c
VUF 5401	2-DMAF	-CH2-S-(CH2)2-	NH-C(=S)-NH-	methyl	117 (41-194)b
VUF 5550	2-DMAF	-(CH2)6-	NH-C(=N-CN)-NH-	methyl	120 (59-181)
VUF 5499	2-DMAF	-(CH2)4-	NH-C(=O)-	methyl	126 (79-174)
VUF 5509	2-DMAF	-(CH2)4-	NH-	phenyl	131 (31-232)h
VUF 5733	4(5)-IM	-(CH2)2-	NH-C(=N-CN)-NH-	methyl	137 (121-153)e
VUF 5500	2-DMAF	-(CH2)3-	CH2--	phenyl	143 (103-255)
VUF 5496	2-DMAF	-(CH2)4-	NH-C(=N-CN)-NH-	methyl	159 (36-283)h
Burimamide	4(5)-IM	-(CH2)4-	NH-C(=S)-NH-	methyl	184 ± 16d
VUF 5261	4(5)-IM	1,4-piperidinyl	-C(=S)-NH-	methyl	201 ± 8d
VUF 5520	2-DMAF	-(CH2)4-	NH-C(=O)-	phenyl	203 (154-252)
Norburimamide	4(5)-IM	-(CH2)3-	NH-C(=S)-NH-	methyl	217 ± 29d
Improgan	4(5)-IM	-(CH2)3-	NH-C(=N-CN)-NH-	methyl	276 (193-359)f
VUF 5554	2-DMAF	-(CH2)6-	NH-C(=O)-NH-	phenyl	284 (243-324)
VUF 4684	4(5)-IM	-(CH2)4-	NH-C(=S)-NH-	cyclohexyl	285 ± 21d
Metiamide	4-Me-5-IM	-CH2-S-(CH2)2-	NH-C(=S)-NH-	methyl	370 ± 39d
Cimetidine	4-Me-5-IM	-CH2-S-(CH2)2-	NH-C(=N-CN)-NH-	methyl	464 ± 89d
VUF 5495	2-DMAF	-(CH2)4-	-NH2	-	689 (316-1,062)h
VUF 5547	2-DMAF	-(CH2)6-	NH-C(=O)-NH-	4-iodophenyl	> 149
VUF 5548	2-DMAF	-(CH2)4-	NH-C(=O)-NH-	4-iodophenyl	> 226
Thioperamide	4(5)-IM	1,4-piperidinyl	-C(=S)-NH-	cyclohexyl	> 342d
VUF 8299	Phenyl	-CH2-S-(CH2)2-	NH-C(=N-CN)-NH-	methyl	> 403d
VUF 5394	1-IM	-(CH2)3-	NH-C(=S)-NH-	methyl	> 504c
VUF 8298	2-Pyridinyl	-CH2-S-(CH2)2-	NH-C(=N-CN)-NH-	methyl	> 602d
VUF 4741	4(5)-IM	-(CH2)6-	NH-C(=S)-NH-	phenyl	partial agonistd
VUF 5262	4(5)-IM	1,4-piperidinyl	-C(=S)-NH-	phenyl	partial agonistd
VUF 6912	4(5)-IM	-(CH2)6-	NH-C(=N-CN)-NH-	methyl	partial agoniste
VUF 5393	1-IM	-(CH2)3-	NH-C(=CH-NO2)-NH-	methyl	toxicc,g

^aHot plate ED₅₀ values (nmol, 10 min after drug) were estimated by non-linear regression following intracerebroventricular injection. Data from the present study (shaded cells) were derived from at least three doses of each drug (n=6-12). Error estimates are specified as either 95% confidence intervals (in parentheses) or as ± SEM. Results from the tail flick test (not shown) were virtually identical with hot plate data.

^bPreliminary report of these results¹⁵.

^cLiterature value¹¹.

^dLiterature value³.

^eLiterature value¹².

^fAverage of two studies³,¹².

^gToxicity observed below antinociceptive doses.

^hDose-response curve had a steep slope, yielding large confidence intervals for these drugs. Structures for the Ar substituent abbreviations (left) and spacer Y abbreviations (right) are given below.